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text:
The End of the Impotence: Theriot's Homerless Streak is Broken
Ryan Theriot's grand slam on Friday put the Cubs ahead to stay, as did his first-inning home run on Saturday.
Friday's blast ended a string of 620 at-bats and 157 games in which Theriot had failed to homer. In terms of GP, Theriot's homerless string was the 15th longest among Cub non-pitchers since 1954.
The list of 15 follows:
- Don Kessinger (5/15/66 through 9/3/68) 404 G
- Larry Bowa (5/13/83 through 8/11/85), 310 G
- Mick Kelleher (4/17/76 through 10/5/80), 304 G
- Don Kessinger (8/16/72 through 7/11/74), 279 G
- Rey Sanchez (8/30/92 through 7/2/95), 256 G
- Richie Ashburn (4/12/60 through 10/1/61), 255 G
- Ivan DeJesus (5/28/80 through 10/4/81), 223 G
- Don Kessinger (7/13/74 through 9/28/75), 220 G
- Don Kessinger (4/24/70 through 6/11/71), 202 G
- Doug Dascenzo (5/5/91 through 10/4/92), 197 G
- Don Kessinger (7/4/71 through 8/13/72), 185 G
- Scot Thompson (7/4/80 through 7/19/83), 179 G
- Larry Bowa (4/5/82 through 5/7/83), 165 G
- Jimmy Stewart (4/18/65 through 5/14/67), 158 G
- Ryan Theriot (4/16/08 through 4/30/09), 157 G
That's a whole lotta shortstops and a whole lot named Kessinger. For what it's worth, Theriot had a far higher batting average (.311), on-base percentage (.387), and slugging percentage (.360) during his homerless streak than anyone else in this group.
And now, in 2009, he has as many home runs as Derrek Lee and Milton Bradley.
Stats from Baseball-Reference.com Play Index
Re: The End of the Impotence: Theriot's Homerless Streak is ...
and courtesy of ye olde world o' roto:
"Dating back to last year, he had gone 40 straight games (43 including the postseason) without driving in more than one run."
Re: The End of the Impotence: Theriot's Homerless Streak is ...
Wow I never realized Scot Thompson had a complete lack of power. I remember him as a pinch hitter on some of the first Cubs teams I remember seeing around 82 or 83. And this was a guy who played first base quite a bit. A player like this today would pretty much be laughed out of the league. Even Doug Mienkiewicz hit doubles in his best years.
Thompsons career OPS was 640 thats sub-Neifi/Miles.
Thompson had 66 career extra base hits in 1391 at bats, to go along with only 17 stolen bases and 97 career walks. But he also only struck out 141 times.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
I have two Scott Thompson memories.
He crashed into the ivy head first catching a fly ball came out with broken collar bone.
He doubled in Philadelphia and he made the turn and kind of walked back to second and Larry Bowa came running up behind him with the ball and tagged him out.
He was kind of the perfect Cub in those days.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
Just as a short point of comparison:
A. 14 HRs in 8,529 MLB PAs
B. 17 HRs in 548 MLB PAs
A. Kessinger
B. My favorite insane pitcher
Re: The End of the Impotence: Theriot's Homerless Streak is ...
Whose got the Cubs record for HR's in consecutive games? Was it Ryno's streak in '89? I think Theriot is going to give it a run.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
Hack Wilson, Sammy Sosa, and Sandberg all had streaks of 5.
Re: Lineup
Ross, Gload or Ross Gload?
Punctuation joke. Funny stuff.
Re: The End of the Impotence:
in the title and not one Cialis or Viagra joke...
Re: The End of the Impotence:
I wish the end of the impotence meant the Indians gave us back Kerry Wood. Or at least his wife. Yeah, that might do it.
Re: The End of the Impotence:
Meet Bob. Bob is feeling pretty good because Bob swings a big stick. He handles a big bat. Opposing players know that Bob provides some stiff competition.
Re: The End of the Impotence:
I thought it was a pun on the Don Henley song...
Re: The End of the Impotence:
could be...I see impotence and I want to see limp dick jokes.
Re: The End of the Impotence:
Skinny Dick sat today...
Re: Z hurt
See? I said that they shouldn't let Zambrano try to hit, he should just strike out every time up.
Re: Z hurt
Z can't be hurt, I have been told many times the last couple days that the chances of him getting hurt hitting and running are so small that it is stupid for me to even bring it up...:)
Firstly, let's hope it is not serious and that this stops Lou from using him as a PH anytime in the near future.
Re: Z hurt
Did he get hurt PHing?
Re: The End of the Impotence: Theriot's Homerless Streak is ...
Foxsports's blurb on Bradley:
News: Bradley homered in Chicago's 8-2 loss to Florida in 10 innings thursday night.
Two bits of really important news there. The first is that crunch's spelling of 'thursday' is now the agreed one, but more bizarely, somehow Bradley homered 10 times, but the Cubs only scored 2 runs. Maybe the umps are out to get him.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
capital letters are for jerks.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
evidently if you throw marmol 64 pitches over 3 days in a row he needs more than just 1 day off.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
awwwright...leadoff homer, bb...K, popout, K...
What a play by Fukudome to end the game
Cubs Win, 3 of 4, 5 of 8....see, they're awesome
if Z has to sit....
I believe Esmalian Caridad was scheduled to start today for Iowa...looks like it might have been a rainout though.
Re: if Z has to sit....
He pitched 3 scoreless innings in the suspended game.
Chris Carpenter had a good day for Peoria, and Starlin Castro and Robinson Chirinos hit their first homeruns of Daytona's season.
Anybody else think Caridad sees the majors this year?
Re: if Z has to sit....
'Grit and Gravy' could have been another name for Theriot and Fontenaught.
We're going to have to come up with some nickname for Chris Carpenter, being that his name is already taken... keeps confusing me. If there is a pitcher called up, I'd suspect he gets the chain re-action promotion to La Florida.
Re: if Z has to sit....
Groundball machine Ryan Searle pitched well again for Daytona today, dropping his ERA to 1.88, which would make another logical promtion. TN got rained out as well.
Re: if Z has to sit....
How 'bout "Jesus Carrying Wood Craftsman"? Too wordy?
Re: if Z has to sit....
Musket says it's day to day... however without him to PH, I hope AramRam is ready to go tomorrow or they may have to use the DL just because of the bench crunch.
Re: if Z has to sit....
"...or they may have to use the DL just because of the bench crunch."
Alternatively, they could release or DFA Gathright in order to call someone up. They didn't even use him to pinch run today when Z got hurt, choosing to turn to Harden instead. Of course, I suppose one could blame that ON the bench crunch, rather than considering it another situation that exacerbates the bench crunch. To be fair, though, Harden is fast. Funny fast.
Re: if Z has to sit....
Yeah, Harden runs like someone using a hack in an FPS game. I'd be really interested in him and Gathright doing a foot race to first.
I would guess that you're right about saving the 'bat' of Gathright for later in the game.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
SB: C Crawford 6 (17)
They must have had throwback to 1985 day in Tampa.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
Submitted by Charlie on Sun, 05/03/2009 - 4:15pm.
He pitched 3 scoreless innings in the suspended game.
Anybody else think Caridad sees the majors this year?
CHARLIE: I believe Esmailin Caridad will get promoted to the big leagues sometime this year. If the Cubs were to bring him up to replace Zambrano for a start or two and then option him back to Iowa, it wouldn't be any big deal, because Caridad gets four minor league option years since he has completed only one "full season" (2008) going into 2009. And he is 25, so he is probably as physically and emotionally mature now as he's ever going to be. He was developed by the Hiroshima Carp at their Dominican academy, so he knows all about the rigors of hard work. Also, Piniella apparently liked what he saw of Caridad in ST, keeping him around a little bit longer than was expected.
But Randy Wells would probably be the best bet to succeed at the big league level as a starter right now. A rubber-armed convetrted catcher and a Jon Lieber clone, Wells is 26, he's already on the 40-man roster, he throws strikes, he gets a lot of ground balls, and he has pitched well at Iowa so far this season. But he also hasn't pitched for several days because of the rain out at Memphis this weekend, so he might be out of synch to replace "Z" in the Cubs rotation on Friday.
It's also possible that if Zambrano can't make his next start, that Jeff Samardzija will start in his place, and Chad Fox will get brought up from Iowa. C. Fox has pitched very well at AAA and appears to be healthy, but even if he were to break down later this season, the Cubs could always put him on the DL and use his spot on the 40-man roster as a post-season roster exemption (like they did last year), presuming the Cubs make it to the NLDS.
Re: The End of the Impotence: Theriot's Homerless Streak is ...
Can it possibly be a coincidence that if you rearrange the letters in Theriot and add a D at the end, you get Thteroid, which is how a person with a speech impediment would say steroid? Spooky...
Re: The End of the Impotence: Theriot's Homerless Streak is ...
The New Logo
I really like it. Would suggest that you put slightly recessed boxes around all the letters, and pull the 'E' forward so it doesn't look like an 'F', or do the new letter with the final 'R', since that's how a scoreboard operator would probably do it.
Belly of the Beast
hybrid from the Muskat article linked above and the Sun-Times (Toni Ginnetti):
"I tried to initially [take Zambrano out], but he told me that it was more of a cramp than anything else," Piniella said. "After a pitch, he realized it was more than that. I tried to get him out initially, and he talked me out of it.
At first he tried to convince trainer Mark O'Neal and Piniella it was only a cramp. After one pitch to the next batter, Alfonso Soriano, ''he realized it was more,'' Piniella said. ''We did the right thing by getting him out.''
Zambrano then slowly walked back to the dugout. The problem is in the "belly" of the (left) hamstring, Piniella said.
Zambrano's next scheduled start is Friday in Milwaukee.
''I'd say it's in jeopardy,'' Piniella said. ''And if I had to guess, I'd say no. We'll see. I'd guess we'd have to do something to bring up a starter, but let him get his [MRI].''
MRI results to be released today (MRI was done sunday after the game).
Recent comments
Who is this Arrieta guy? Can I get the old one back please?
Well, this is, once again, the whole season for the Sox.
...and the Bryant RBI jinx continues in the 3rd....crap.
bryant's in the dugout filling a police report BECAUSE HE JUST GOT ROBBED.
f'n cabrerra...
chapman showing up and available tomorrow night.
i'm sure he'll be a bit hit. hope he doesn't choke. dude has a rifle for an arm. he'll add a bit of punch to the bullpen.
the 'crosstown classic' sure has lost it's magic with interleague. the excitement level is barely noticable...maybe it's a bit more hype in the city, itself.
Well he didn't leave a mark so its not that bad.
Fuck that.
He choked her.
Her brother tackled him to separate him.
He cooled off by shooting his gun in the garage.
I don't have to like him on the team I follow.
And you are others are free to not give a shit about his personal misgivings if you so choose as well.
Sure, no marks and some inconsistencies in the witness's statements. But firing your gun into garage wall immediately after an argument and punching out your car window is still threatening and out of control behavior. There was certainly enough for MLB to think it warranted a 30-game suspension.
I'd prefer they be flexible with the closing situation depending on matchups. You're not really adding a lefty reliever if you use him strictly as a closer.
Stockpiling young talent isn't only for trading for someone like Chapman though. Even with an elite closer winning the World Series is basically a crap shoot so the key is to get to the playoffs as much as possible and not just mortgage everything on one year. Once you get there an elite bullpen certainly helps but the playoffs can be won by one hitter or starting pitcher getting hot (Murphy, Molina, Baumgardner) and a closer might not be able to stop that.
I'm also not crazy about press convictions. As the police report noted, there were no marks on the lady in question. There's a TMZ link (of course) to her police pictures, as well.
I think the only way this trade goes real bad is if Cubbery intervenes and Chapman is suddenly bad for some reason.
I am right there with you closing in on 60.
I don't care that much about "mortgaging" one player who is not only blocked by two guys, but is not ready to hit the majors for at least a couple years.
There is no reason why this team, this year, can't have a real shot at something NONE of us have experienced.
Further, I don't feel that even if they fall short that they have ruined their farm system.
I have made my opinion clear here, with others, Warren was shit on the Cubs save one spot start.
Trading for Warren, Warren sucking, getting Warren back for Chapman plus 3 prospects, sounds like Revenge of The Yankees on the former Boston executive. Old rivalries never die.
I pray to the heavens above Chapman doesn't suck for some reason, or he'll be booed out of town faster than a Todd Hundley revival meeting.
I'm kind of nostalgic for the Schwarber-for-Miller rumors.
This offseason, after some ridiculous playoff run and Chapman saving every game from here until the end of the postseason striking out 27/9innings, I welcome anyone to quote this thread and call me a dummy: I hate this trade, and my hate is 2 parts Chapman makes this team less likeable and 1 part that's a ridiculous overpay for 30 regular season innings and, at tops, 10 postseason innings. Already hoping they don't extend him.
btw...Thanks AZ Phil. I'm really enjoying your take on this trade.


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text:
Northern Ireland
Christian protesters fail to halt Belfast Pride
Post your comment
Comments on this article are now closed.
Reader comments
"As the parade passed, they turned their backs and bowed their heads."
So their bottoms were in the air.
Quite appropriate since the members of the Free Presbyterian cult are likely to be closet cases. People who are obsessed with gay sex tend to be gay after all.
Free Presbyterian Church, eh?
Typical Pick n Mix bigots.
wheres the christian love, compassion, loving ur neighbor etc?
Love, compassion and loving your neighbour are alien concepts to the Free Presbyterians. Their stock in trade is hatred, division, sectarianism and intolerance.
I am old enough to remember parades i Belfast ending in death, blood and gore; all apparently in the name of religion! Gay Pride, people enjoying themselves, having fun and totally NON VIOLENT!
I wonder if some of these nutcases were also at London Pride – mostly the placard wavign cranks had an Ulster accent. I quite enjoyed whipping up the crowd around me to hurl abuse back at them :-)
Ulster, green and orange united, says no to sodomy!
Not true Fenian. Crazed extremist bigots from the DUP are certainly opposed to sodomy (although I imagine they are the most fervent practitioners – always the same story with the extremist bigots). All other people seem pretty cool about the gaylove.
@Simon Murphy – nice one – I agree with both of your posts – took the words out of my mouth.
Carrying placards that read "God hates fags" – now that's not offensive at all – but seeing people defending their humanity, now that's just downright awful, isn't it? How dare they love each otber when they should be holding hateful placards and protesting against love!
I walked in Saturday's Belfast Pride Parade, and had a THOROUGHLY GOOD TIME! The so-called 'Christian protests' were truly a total non-event – barely noticeable if you didn't know where to expect them, [same locations as last year] and when you reached that point they were SO easy to ignore. The first group, in the park beside the Cathedral (but not associated with the Cathedral) simply turned their backs and started to pray – hardly worthy of the name 'Protest'. Let's face it, a banner that proclaims that God so loved the World …(John 3:16) is hardly 'anti-Gay' – more 'pro-Gay' if anything since Gays always have been part of the world!! A banner that proclaims "Remember the Sabbath Day to keep it Holy" is hardly a convincing protest on a Saturday afternoon!
The second group of protesters at City Hall were louder and more vocal, but the general public simply stood between them and the parade so really their efforts came to nothing.
It seems to me a GREAT pity that the media [Pink News included] sees fit to portray the afternoon as some kind of conflict between the Gays and the Christians – it really wasn't that at all. It was a celebration by the Gay community of who and what they are; and the tens of thousands of smiling faces lining the route, enjoying the spectacle is the real story. The public really enjoyed the spectacle – I watched the crowds as I walked along for about 1.5 hours through the city centre and I can honestly say that I didn't detect a single disapproving scowl – we were cheered, clapped and smiled at as we went along, maybe one or two bemused people not sure what was going on, but certainly NO hostility that I could detect.
As for the protesters … well, no doubt they went home filled with self-righteousness because they had 'stood up for the Gospel' – well, sorry to disappoint them but their efforts were entirely in vain … but then they probably knew that before they left home – if they were entirely honest. They were nothing more than the 'verbal masturbators' of the afternoon – those who get their kicks from the sound of their own voices, voicing their own opinions (and prejudices) but produce absolutely NOTHING of any value. I'm sure even The Almighty yawned with boredom when He had to listen to them.
Finally, GREAT credit to the organisers who did a superb job at organising a most enjoyable afternoon and a superb parade, who showed more Christianity towards those who wished to protest than the Christian protesters showed to their fellow human-beings.
Belfast Pride was a SUCCESS!!! A MOST ENJOYABLE AFTERNOON!!!!!
I was there as well and for the sixth time and I had a great time as usual. AndySam above is correct that the protesters were a total non-event and a really good time was has by all.
The way that everyone comes together for the parade is an amazing buzz and, although we didn't have Iris Robinson's idiotic comments like last year to polarise us, it was still great to see people of all varieties lining the street and cheering us on.
Well done everyone!
Fenian, don't you mean says "Ulster, green and orange united, no to stupidity!"
…there's a lot of your religious crap up in that Provence. Isn't it time for you and your kind to grow up and join the Republic and Great Britain in the 21st century?
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More than 80 percent of schools in America use toxic pesticides as a preventative measure, whether it's needed or not. Mark Lame, an entomologist and professor at Indiana University's School of Public and Environmental Affairs, believes this is an entirely unnecessary practice that carries more risks than benefits to students and faculty.The most widely used pesticides are, in fact, nerve poisons. They cause uncontrolled nerve firing, and disrupt the delicate hormone systems. The link between pesticide exposure and health problems in children is already well established. Research has connected these endocrine-disrupting pesticides to health problems such as ADHD, autism, and infertility -- all of which are on the rise.Professor Lame says pest problems are better managed through an integrated approach -- by preventing the conditions that attract pests into school facilities in the first place.Lame serves as a consultant for schools around the country, helping them reduce the toxic load by implementing his Integrated Pest Management (IPM) process.Science Daily July 21, 2007
Even though schools believe they are doing the right thing by eliminating bugs and pests from the premises, they are actually putting children at serious risk for long-term damage.
The United states uses about 888 million pounds of pesticides and herbicides each year. That's the equivalent of three pounds of toxins for every man, woman and child, and the current pesticide load on your body is surely taking its toll.
Among the many problems they cause include:
Neurological Damage in Children is a Growing Problem
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text:
|Name: _________________________
|Period: ___________________
This test consists of 5 short answer questions, 10 short essay questions, and 1 (of 3) essay topics.
Short Answer Questions
1. What is the worst enemy abuse that Goodrich remembers seeing?
2. What happens as Waterbull sits under his hooch looking at a picture?
3. Who is hit as Snake's company has point patrol in Go Noi?
4. What is Hodges thinking as he watches his men dying in Arizona Valley?
5. What is Hodges thinking when he sees that Flaky has been shot?
Short Essay Questions
1. Who is wounded during enemy fire in An Hoa?
2. Describe the circumstances when Cat Man arrives in America from Mexico?
3. What is the result of the investigation of the banana trees just off the trail that Hodges' men are following?
4. Why does Snake argue with Austin's order to send a platoon on the other side of the wire at the tree line for LP?
5. What does Hodges consider unfair when he confronts the enemy in the village?
6. What problems does Cannonball encounter in boot camp and Vietnam?
7. Why do the men always dig new fighting holes, rather than use old holes that they find?
8. What does Bobby Hodges awaken to his first night in Vietnam?
9. What does Bagger explain to his Marine buddies when he gets back from R&R?
10. Why does Cannonball decide to join the Marines instead of the Army?
Essay Topics
Write an essay for ONE of the following topics:
Essay Topic 1
1) What role does racism play in the novel?
2) Explain the relevance of the Black Shack and the effect it has on both the white and black soldiers.
3) Describe the unrest that racism causes between white and black men fighting and relying upon one another in battle.
4) Specifically, analyze the moral dilemma that Cannonball faces because of racism during the war.
Essay Topic 2
Naturalism emphasizes that humans act by instinct, similar to animals, or compulsively driven by circumstances beyond their control.
1) Summarize three figurative comparisons that suggest either the animal nature of Snake or the compulsive nature of his actions.
2) Explain the answers as examples of Naturalism.
Essay Topic 3
1) What images does Webb use to describe the Killer Fields as the men cross through them?
2) How do these images have different meaning for different people?
This section contains 693 words
(approx. 3 pages at 300 words per page)


text:
Dr. He and A.P. Popkie contributed equally to this work.
Research Article
Gsk3β is required in the epithelium for palatal elevation in mice
Version of Record online: 27 OCT 2010
DOI: 10.1002/dvdy.22466
Copyright © 2010 Wiley-Liss, Inc.
Developmental Dynamics
Volume 239, Issue 12, pages 3235–3246, December 2010
Additional Information
How to Cite
He, F., Popkie, A. P., Xiong, W., Li, L., Wang, Y., Phiel, C. J. and Chen, Y. (2010), Gsk3β is required in the epithelium for palatal elevation in mice. Dev. Dyn., 239: 3235–3246. doi: 10.1002/dvdy.22466
Publication History
- Issue online: 22 NOV 2010
- Version of Record online: 27 OCT 2010
- Manuscript Accepted: 23 SEP 2010
Funded by
- NIH. Grant Numbers: R01 AG031883, R01 DE14044
- Abstract
- Article
- References
- Cited By
- Gsk3β;
- cleft palate;
- palatal elevation;
- palate development
In Wnt/β-catenin signaling pathway, Gsk3β functions to facilitate β-catenin degradation. Inactivation of Gsk3β in mice causes a cleft palate formation, suggesting an involvement of Wnt/β-catenin signaling during palatogenesis. In this study, we have investigated the expression pattern, tissue-specific requirement and function of Gsk3β during mouse palatogenesis. We showed that Gsk3β is primarily expressed in the palatal epithelium, particularly in the medial edge epithelium overlapping with β-catenin. Tissue-specific gene inactivation studies demonstrated an essential role for Gsk3β in the epithelium for palate elevation, and disruption of which contributes to cleft palate phenotype in Gsk3β mutant. We observed that expression of Aixn2, a direct target gene of Wnt/β-catenin signaling, is ectopically activated in the mutant tongue, but not in the palate. Our results indicate that Gsk3β is an intrinsic regulator required in the epithelium for palate elevation, and could act through a pathway independent of Wnt/β-catenin signaling to regulate palate development. Developmental Dynamics 239:3235–3246, 2010. © 2010 Wiley-Liss, Inc.
Cleft palate is a common birth defect in humans, with a prevalence ranging between 1/1,000 and 1/700 (Koillinen et al., 2005). The development of mammalian secondary palate is a multiple-step process and disruption at any step, environmentally or genetically, could result in a cleft palate formation. In mice, the palatal shelves protrude from bilateral maxillary processes at embryonic day (E) 11.5, and grow vertically along the developing tongue from E12.5 through E14.0. Subsequently, they elevate, meet, and fuse at the midline, ultimately form an intact palate shelf at E14.5 (Ferguson,1988). Palatal shelf elevation is a rapid process, accompanied by extracellular matrix accumulation within the palatal shelf and movement of other craniofacial structures. Impaired palatal shelf elevation, along with defective palate growth and fusion, comprises major causes for cleft palate formation (Ferguson,1988; Gritli-Linde,2007). It has been proposed that palate elevation is triggered by the intrinsic erectile forces, from both palatal mesenchyme and epithelial covering, and the extrinsic influence, such as coordinated movement of adjacent craniofacial and oral structures including descending of the tongue (Ferguson,1988). It is thought that mesenchymal cells provide erectile elevation force and the epithelial covering constrains and guides the force to appropriate direction to manage the elevation (Bulleit and Zimmerman,1985; Ferguson,1988). Studies using gene-targeting mice have demonstrated that failed palatal shelf elevation could be attributed either to intrinsic elevation defects or to other oral structure deformation (reviewed in Gritli-Linde,2007). In addition, anomalous fusion of the palatal shelves with the tongue or the mandible also leads to elevation defect (Rice et al.,2004; Alappat et al.,2005; Casey et al.,2006; Xiong et al.,2009).
The β-catenin–mediated Wnt canonical (Wnt/β-catenin) signaling pathway plays pivotal role in regulating multiple events of embryonic development. This signaling cascade is activated by Wnt ligand binding to the Frizzled (Fz) transmembrane receptors and LRP5/6 co-receptors. The binding disassembles in the cytoplasm the β-catenin destruction complex, which is composed of glycogen synthase kinase-3β (Gsk3β), Axin, and adenomatous polyposis coli (APC). Consequently, β-catenin accumulates and translocates into the nucleus, where it binds to LEF/TCF co-transcription factors and activates target genes expression (van Amerongen and Nusse,2009). In the absence of Wnt ligands binding, β-catenin is phosphorylated by Gsk3β and is further processed to degradation. Gsk3β acts as a negative modulator of Wnt/β-catenin signaling.
Two highly related Gsk3 protein homologues have been identified in mammals: Gsk3α and Gsk3β, which are encoded by two genes (Frame and Cohen,2001; Doble and Woodgett,2003). First recognized by its function in regulating glycogen synthase activity, Gsk3β has been shown to play a role in several cellular processes, including modulating the Wnt/β-catenin signaling (Embi et al.,1980; Frame and Cohen,2001; Grimes and Jope,2001; Doble and Woodgett,2003). During mouse embryonic development, Gsk3β is essential for liver cell survival as well as palate formation (Hoeflich et al.,2000; Liu et al.,2007). Although the specific function for Gsk3α remains unknown, it has been shown that Gsk3α and Gsk3β function redundantly in regulating Wnt/β-catenin signaling in embryonic stem cell lines (Doble et al.,2007).
Wnt/β-catenin signaling has been implicated in the development of various tissues and organs, including the craniofacial structures (Grigoryan et al.,2008). Although a direct role for β-catenin in the regulation of palate development awaits evidence, β-catenin expression was indeed observed in the palatal epithelium and possibly in the mesenchyme as well (Martinez-Alvarez et al.,2000; Tudela et al.,2002; Nawshad and Hay,2003; He et al.,2008). In fact, many lines of recent evidence suggest an involvement of the β-catenin–mediated Wnt canonical signaling in palatogenesis. For example, mice deficient for either Wnt9b, or Lrp6, or Wnt5a exhibit a cleft palate phenotype (Yang et al.,2003; Carroll et al.,2005; He et al.,2008; Song et al.,2009). Wnt11 was found to be expressed in the palatal epithelium and its function is indispensible for palate fusion (Lee et al.,2008). In addition, mutations in WNT5A or WNT3 have been correlated to a cleft palate defect in humans (Blanton et al.,2004; Niemann et al.,2004). All these lines of evidence suggest a role for Wnt canonical signaling in palatogenesis.
We report here that Gsk3β is primarily expressed in the palatal epithelium, particularly in the medial edge epithelium (MEE) region overlapping with β-catenin. To determine the tissue-specific requirement of Gsk3β in palatogenesis, we have generated Gsk3β conditional knockout mice and demonstrated that Gsk3β is specifically required in the epithelium for normal palatogenesis. Mice deficient for Gsk3β exhibit an impaired elevation of the palatal shelves, leading to a complete cleft of secondary palate. We also detected Axin2 expression in the developing palate, and showed that its expression is not altered in the Gsk3β mutant palate. Our results support the idea that Gsk3β is an intrinsic regulator of palate elevation, and its absence does not alter the Wnt/β-catenin signaling pathway in the developing palatal shelves.
Expression of Gsk3β Is Enriched in the Epithelium of Developing Palate
Although it was proposed that Gsk3β is ubiquitously expressed in all cells, tissue-specific expression of this gene has been reported (Ciaraldi et al.,2006). To investigate the role of Gsk3β during palatogenesis, we first examined its expression pattern in the developing palate by in situ hybridization. Our results showed that, at E12.5, Gsk3β is expressed both in the anterior and posterior palate, at a higher level in the palatal epithelium, and an above background level of expression in the palatal mesenchyme (Fig. 1A,C). At E13.5, Gsk3β is expressed in a pattern similar to that in E12.5 embryo, but its expression is mainly restricted to the MEE (Fig. 1B,D). This expression pattern overlaps with that of Catnb, which encodes β-catenin, the central mediator of the Wnt canonical signaling (He et al.,2008). In addition, Gsk3β expression was also found in the epithelium of the developing tongue (Fig. 1). These results suggest that Gsk3β may modulate Wnt/β-catenin signaling function during palate development.
Gsk3β Is Specifically Required in the Epithelium to Regulate Palate Development
It was reported previously that Gsk3β-deficient mice exhibit a cleft palate defect, but the mechanisms underlying this phenotype still remained unknown (Liu et al.,2007). To extend the finding and examine the morphological and molecular defects that lead to the complete cleft palate formation in Gsk3β mutant mice, we created by gene targeting in embryonic stem (ES) cells a Gsk3β conditional allele (Gsk3βF/+) in which exon 2 was flanked with the LoxP sequences (Fig. 2). The targeted locus in ES cells and germline transmission were confirmed by Southern blotting (Fig. 2B), mice heterozygous or homozygous for the conditional allele were genotyped by a polymerase chain reaction (PCR) -based method (Fig. 2). To create a null Gsk3β allele (Gsk3β+/−), we crossed Sox2Cre mice to Gsk3βF/+ mice to delete exon 2, which encodes the Gsk3β protein domain responsible for the kinase activity. While mice heterozygous for Gsk3β mutation appear normal and fertile, Gsk3β−/− mice, obtained by intercrosses between Gsk3β+/− mice, showed a complete cleft palate defect and died within 24 hours after birth (Fig. 3B), a phenotype identical to what was reported previously (Liu et al.,2007).
Histological analyses of the developing palate of Gsk3β−/− mice at multiple stages revealed a normal development of the palatal shelves before E13.5, as compared to the wild-type controls (Fig. 3D,E,G,H). At E14.5, the palatal shelves have elevated to a horizontal position and fused in the middle line in the wild-type controls (Fig. 3J). In Gsk3β−/− embryo, however, the palatal shelves remained in the vertical position and failed to elevate to the position above the tongue (Fig. 3K). At E18.5, the mutant anterior palatal shelves eventually elevated to a horizontal position but failed to make contact (data not shown), and the posterior palatal shelves remained in a vertical orientation and never elevated (Fig. 3M,N). The delayed/failed elevation of palatal shelves is, therefore, the cause of cleft palate phenotype in Gsk3β−/− mice.
Because Gsk3β expression is detected primarily in the palatal epithelium, and in the mesenchyme as well, we next sought to address the tissue-specific requirement of Gsk3β function during palate development. We chose to use two established transgenic lines Pitx2Cre and Osr2Cre to abort Gsk3β function in tissue-specific manners in the developing palate. Pitx2Cre and Osr2Cre mice have been used in previous studies to delete LoxP-flanked genes in the palatal epithelium and mesenchyme, respectively (Lan et al.,2007; Xiong et al.,2009). We found that Osr2Cre;Gsk3βF/F mice survived postnatally and showed normal palate formation (5/5). In contrast, among 14 Pitx2Cre;Gsk3βF/F mice examined, 11 exhibited a complete cleft of the secondary palate, phenocopying the defect in the Gsk3β−/− mice (Fig. 3C; and data not shown). The incomplete penetrance of cleft palate phenotype in Pitx2Cre;Gsk3βF/F mice could be attributed to variation in Cre activity or expression timing by the Pitx2Cre transgenic allele in different embryos. Nevertheless, histological examination of Pitx2Cre;Gsk3βF/F embryos revealed the development of the palatal shelves do not exhibit any malformation until E13.5 (Fig. 3F,I). However, at E14.5, similar to defects found in Gsk3β−/− mice, the Pitx2Cre;Gsk3βF/F palatal shelves failed to elevate (Fig. 3L). While the anterior palatal shelves did elevate at E18.5, the posterior palatal shelves remained at the vertical position (Fig. 3O). These results indicate that Gsk3β function is required in the palatal epithelium during palate development, and Gsk3β acts in the palatal epithelium to control palatal shelf elevation.
To rule out the possibility that the failure of palate shelf elevation in Gsk3β mutants is due to extrinsic defects such as malformation of the tongue and mandible, we performed in vitro organ culture on a rotary apparatus. Individual embryonic head with removal of mandible of E13.5 embryos harvested from mating of Gsk3β+/− mice was cultured for 24 hr, and then processed for histological examination after genotyping. As shown in Figure 4, after 24 hr in culture, the wild-type controls exhibited elevated palatal shelves (9/9); however, the mutant palatal shelves remained at the vertical position (10/10). These results indicate that intrinsic defects in the absence of Gsk3β in fact contribute to the failure of palate elevation.
Gsk3β Is Required for Normal Cell Proliferation and Palatal Epithelial Cell Survival
Defects in cell proliferation and/or survival have been shown to impair normal development of the palatal shelves, leading to the cleft palate formation (Gritli-Linde,2007). To determine if these cellular processes were affected in Gsk3β−/− palate, we performed bromodeoxyuridine (BrdU) labeling and TUNEL assays on E12.5 and E13.5 palatal shelves of wild-type controls and mutants. Our found comparable cell proliferation rates (P > 0.05) in the mesenchyme between the controls and mutant at E12.5 and E13.5 (Fig. 5A,B; and data not shown). In contrast, cell proliferation rates in the epithelium showed significant difference statistically, with a enhanced rate at E12.5 and a decreased level at E13.5 (Fig. 5G). This altered cell proliferation rate in the mutant epithelium is consistent with Gsk3β expression domain in the developing palatal shelf. In additional, we also observed significantly increased apoptotic cells in the palatal epithelium, including the MEE of the Gsk3β−/− palate at E13.5 (Fig. 5D,F). These results indicate that Gsk3β is implicated in the regulation of cell proliferation and survival during palatogenesis.
Gsk3β Does Not Regulate Palate Elevation Through Shh, Osr2, and PDGF Signaling
To determine the molecular defects in the Gsk3β−/− palate, we examined the expression of several genes that either exhibit an overlapped expression pattern with Gsk3β in the developing palate or have been shown to regulate palate elevation. Among them, Shh is expressed in the MEE and oral palatal epithelium (Fig. 6A,E; Zhang et al.,2002; Rice et al.,2004). Epithelial-specific inactivation of Shh results in abnormal cell proliferation and apoptosis, as well as failed palatal shelf elevation (Rice et al.,2004; Gritli-Linde,2007). Our in situ hybridization results showed that the expression of Shh, as well as that of its direct target Ptch1, was not altered in the Gsk3β−/− palate (Fig. 6B,F; and data not shown), suggesting that the Shh signaling functions upstream of or in parallel to Gsk3β during palate development. Osr2 is expressed in the oral side palatal mesenchyme and inactivation of Osr2 leads to a defect in palatal shelf elevation in mice (Fig. 6C,G; Lan et al.,2004). We found that Osr2 expression was not changed in the Gsk3β−/− palate (Fig. 5D,H). The platelet-derived growth factor (PDGF) signaling has been shown to regulate palate development (Soriano,1997; Tallquist and Soriano,2003; Ding et al.,2004). Pdgfa and Pdgfc, encoding two of the PDGF ligands, were specifically expressed in the palatal epithelium overlapping with Gsk3β (Fig. 6I,K; Ding et al.,2004). Inactivation of Pdgfc in mice causes delayed palatal shelf elevation, and Pdgfa;Pdgfc double knockout mice exhibit a more severe cleft face phenotype, indicating an essential role for these two genes in craniofacial development (Ding et al.,2004). We, therefore, examined the expression of Pdgfa and Pdgfc in the Gsk3β−/− palate. As a result, we did not observe an altered expression of either gene (Fig. 6J,L,N,P). We concluded that Gsk3β did not regulate expression of these genes during the palatal shelf elevation.
Inactivation of Gsk3β Does Not Alter Activity of Wnt/β-Catenin Signaling in Developing Palate
It was reported previously that Catnb expression is detected in the palatal epithelium, overlapping with that of Gsk3β (Martinez-Alvarez et al.,2000; Tudela et al.,2002; Nawshad and Hay,2003; He et al.,2008). It is thus intriguing to determine if Gsk3β modulates the activity of Wnt/β-catenin signaling, and if Wnt/β-catenin signaling is involved in palate development. To this end, we have taken advantage of TOPGAL transgenic reporter line, which has been widely used to detect the activity of Wnt/β-catenin signaling (DasGupta and Fuchs,1999). To detect potentially enhanced and/or ectpoic Wnt/β-catenin signaling activity in the Gsk3β−/− palate, we compounded the TOPGAL transgenic allele onto the Gsk3β−/− background, and compared the β-galactosidase reporter activity in the mutant mice with that in the TOPGAL controls. In the TOPGAL transgenic control at E13.5, while intensive LacZ expression was detected in the lip and incisor regions, we did not observe any β-galactosidase activity in the developing palate (Fig. 7A), consistent with the previous report (He et al.,2008). If Gsk3β regulates palate development by modulating Wnt/β-catenin signaling embryos, one would expect to see an ectopic activity of the Wnt canonical signaling in the palatal epithelium. Surprisingly, we observed neither enhanced β-gal staining in the lip and incisor regions nor ectopic LacZ expression in the developing palatal shelves (Fig. 7B). These results suggest that either Wnt/β-catenin signaling is not operating in the developing palate or the TOPGAL transgenic reporter has a limited sensitivity. To address these concerns, we chose to examine the expression of Axin2, a direct target gene of Wnt/β-catenin signaling and a reliable indicator of active Wnt/β-catenin signaling (Jho et al.,2002; Ontiveros et al.,2008; Wang et al.,2008). In the wild-type controls, we observed a specific Axin2 expression in the MEE, with some expression in the immediately adjacent mesenchyme (Fig. 7C). The expression of Axin2 in the MEE overlaps with that of Catnb and Gsk3β, indicating the presence of Wnt/β-catenin signaling activity in the MEE region. At the level of Wnt/β-catenin signaling activity in the developing palatal shelves, the TOGAL transgenic allele appears to have limited sensitivity. Interestingly, we did not observe an elevated or ectopic Axin2 expression in the Gsk3β−/− palate (Fig. 7D). However, ectopic Axin2 expression was detected in the mesenchyme adjacent to the epithelium in the developing tongue of Gsk3β−/− mice (Fig. 7D). These results thus suggest that the function of Gsk3β in modulating Wnt/β-catenin signaling is compensated in the palate but not in the tongue. Since Gsk3α has been shown to have functional redundancy with Gsk3β in modulating the Wnt/β-catenin signaling in stem cell lines (Doble et al.,2007), we reasoned that Gsk3α could have an overlapped expression pattern with Gsk3β in the developing palate where they function redundantly. In situ hybridization assays showed that Gsk3α was expressed in the palatal epithelium, primarily in the MEE and the oral side epithelium (Fig. 7E). This expression pattern in the developing palate overlapped almost perfectly with that of Gsk3β (Fig. 1). In the developing tongue, Gsk3α expression was detected only in the mesenchyme and the epithelium in the ventral–lateral region, complementary to the ectopic Axin2 expression domain in the Gsk3β−/− tongue (Fig. 7D,E). In the developing palate and tongue of the Gsk3β mutant, we did not observe an altered expression of Gsk3α (Fig. 7F). These data suggest that Gsk3α may compensate for the loss of Gsk3β function in modulating Wnt/β-catenin signaling in the developing palate. We thus concluded that a Wnt/β-catenin signaling independent pathway regulated by Gsk3β is essential for palate elevation during normal palate development.
The β-catenin–mediated Wnt canonical signaling has been implicated in many developmental events. However, direct evidence for an involvement of this signaling pathway in palate development is still lacking. In this study, we reported that Gsk3β is primarily expressed in the palatal epithelium, and its major function in palate development is to regulate palatal shelf elevation. Our Gsk3β conditional knockout mice enable us to determine that Gsk3β is specifically required in the palatal epithelium for palatal shelf elevation. We further demonstrate the presence of Wnt/β-catenin signaling activity in the normal developing palatal shelves, and the activity remains unaltered in the Gsk3β mutant palate. Our studies thus support the idea that Gsk3β is an intrinsic epithelium-expressed regulator of palatal shelf elevation and functions independently of Wnt/β-catenin signaling.
Gsk3β Is an Epithelially Expressed Intrinsic Regulator of Palatal Shelf Elevation
The phenomenon of palatal shelf elevation has been recognized for a long time, but the mechanism of this process remains far from being well understood. It is now widely accepted that palatal shelf elevation is a rapid process, undergoing in an anterior to posterior sequence and being controlled by both intrinsic erectile force and extrinsic influences from other craniofacial structures (Lazzaro,1940; Ferguson,1988). Several mechanisms have been proposed for this process. Considering the intrinsic factors, it has been suggested that hyaluronan differential accumulation, type I collagen distribution, mesenchymal cell alignment, and epithelial covering all provide elevation force during palatal shelf elevation (reviewed in Ferguson,1988). Although the mesenchymal tissue was thought to provide major driving force for the elevation, removal of oral epithelium was shown to inhibit the reorientation of palatal shelves in vitro. The palatal epithelium is thus considered to constrain and direct the elevation force generated by the mesenchymal core during palatal shelf elevation (Bulleit and Zimmerman,1985). Temporally and spatially, palatal shelf elevation occurs coincidentally with the descending of the tongue, and the growth of the mandible and basicranium. Malformation of these structures, therefore, could also prevent palatal shelf elevation as extrinsic factors (Ferguson,1988).
Corresponding to the above-proposed mechanisms for palatal shelf elevation, defects in palatal shelf elevation in gene-targeting mice could be categorized into three major classes. First, the palatal shelf elevation can be impaired by intrinsic defects, as seen in Osr2 or Pdgfc mutant mice (Ding et al.,2004; Lan et al.,2004). Second, palatal shelf elevation could be hindered by abnormal fusion between palatal shelf and adjacent oral structures. For example, in mice deficient for Jagged2, or Fgf10, or Hand2, the palatal shelves abnormally fuse with the developing tongue or the mandible, preventing palatal shelf elevation and causing cleft palate formation (Alappat et al.,2005; Casey et al.,2006; Xiong et al.,2009). Third, malformation of the tongue or mandible could physically block palatal shelf elevation, as it is seen in Hox2a and Gli3 mutant mice (Barrow et al.,1999; Huang et al.,2008). In this study, we show that Gsk3β is expressed and functions in the palatal epithelium. Inactivation of Gsk3β impairs palatal shelf elevation without obvious extrinsic defects (for example, tight contact with the tongue or malformation of the mandible) or abnormal fusion with adjacent tissues. Moreover, the observation that the failure of palatal shelf elevation in the mutant head without mandible in organ culture rules out the possibility of extrinsic effects. These results support the conclusion that Gsk3β is an intrinsic regulator of palatal shelf elevation.
Gsk3β has been implicated in cell proliferation regulation (Force and Woodgett,2008; Kerkela et al.,2008). The absence of Gsk3β results in cardiomyocyte hyperproliferation without influence on β-catenin signaling (Kerkela et al.,2008). Consistent with this line of discoveries, we found an altered cell proliferation rate in the mutant palatal epithelium where Wnt/β-catenin signaling activity remained unaltered. It appears that the role of Gsk3β on cell proliferation regulation in the palatal shelves depends largely on developmental stages. We certainly cannot rule out the possibility that this altered cell proliferation rate, together with enhanced cell apoptosis in the palatal epithelium, may also contribute to the cleft palate formation in Gsk3β mutants.
Gsk3β has been shown to modulate activities of several signaling pathways (Frame and Cohen, 2001). Among them is Shh signaling, which is critical for palate elevation (Gritli-Linde,2007; Lan and Jiang,2009). Our findings show that Gsk3β is expressed overlapping with Shh in MEE (Fig. 1A,C) and the mutants also exhibit palate elevation defect (Fig. 3K,N). Shh signaling is thus potential related to the defective palate development of the Gsk3β mutant. However, our in situ hybridization studies showed an unaltered expression of Shh and its transcriptional target Patch1 in the mutant palate, indicating that Gsk3β does not regulate palatal shelf elevation by controlling Shh signaling activity. The expression of Osr2, Pdgfa, and Pgdfc is neither affected in the Gsk3β mutant palatal shelves. Future studies comparing gene expression profiles in the wild-type and Gsk3β mutant palatal shelves would help to identify downstream targets of Gsk3β in the developing palate.
The role of Gsk3β in palate development seems to vary slightly in different genetic background. In the present study, we have shown that Gsk3β controls palate elevation in an inbred C57BL/6 background. In an outbred CD-1 background; however, Gsk3β deficiency does not affect palate elevation, although it also causes cleft palate defect in the null mutant (Liu et al.,2007). Of interest, in another study by Hoeflich and colleagues (2000), Gsk3β homozygous null mice were reported to die during mid-gestation, a phenotype we never observed in our studies. Thus genetic background appears to exert influence on phenotype severity in the absence of Gsk3β. Such correlations between genetic background and phenotype have been reported for other genes (Dansky et al.,1999; Yang et al.,2005).
Implication of the Wnt/β-Catenin Signaling in Palate Development
The Wnt/β-catenin signaling has been implicated in the formation of many organs (Grigoryan et al.,2008). Several Wnt ligands, including Wnt9b, Wnt5a, and Wnt11, have been shown to play a role in palate development (Yang et al.,2003; Carroll et al.,2005; He et al.,2008; Lee et al.,2008). However, these lines of evidence do not support a direct involvement of the Wnt/β-catenin signaling. This is because, in Wnt9b mutant mice, the cleft palate phenotype is a secondary defect (Lan et al.,2006). Wnt5a was shown to act through a β-catenin–independent signaling pathway to regulate palate development (He et al.,2008). Stronger evidence, though still not direct, came from a recent publication in which cleft lip and cleft palate defects are observed in Lrp6 mutant mice (Song et al.,2009). While the TOPGAL reporter activity is not detectable in the developing palate (He et al.,2008; this study), here we show that Axin2, a direct target gene of Wnt/β-catenin signaling and a sensitive indicator of active Wnt/β-catenin signaling (Jho et al.,2002; Ontiveros et al.,2008; Wang et al.,2008), is expressed in the palatal epithelium and restricted to the MEE region. This expression pattern is overlapped with that of Gsk3β and β-catenin (Fig. 1; He et al.,2008). These results demonstrate the presence of active Wnt/β-catenin signaling in the developing palate. Together with the cleft palate phenotype found in Lrp6 knockout mice, these observations support a role for the Wnt/β-catenin signaling in palate development.
Functional Redundancy of Gsk3β and Gsk3α in Palate Development
The mammalian Gsk3 genes have two homologues, Gsk3α and Gsk3β. Although Gsk3β alone is able to modulate the Wnt/β-catenin signaling, in some cases, inactivation of Gsk3β does not necessarily lead to Wnt/β-catenin signaling up-regulation. For instance, in ES cell lines, Gsk3β and Gsk3α have been shown to function redundantly in modulating Wnt/β-catenin signaling (Doble et al.,2007). Wnt/β-catenin signaling activity, which is assessed by the expression of Axin2 transcripts and TCF reporter, is not significantly elevated until three of the four Gsk3 alleles are depleted (Doble et al.,2007). In mouse embryonic fibroblasts, on the other hand, loss of Gsk3β function itself enhances Wnt/β-catenin signaling activity (Kapoor et al., 2008). The differential outcome of Gsk3β ablation in the embryonic stem cells and fibroblasts may reflect the differential expression of Gsk3α in these two types of cells. Of interest, we found that Gsk3α is expressed in a pattern overlapped with that of Gsk3β in the developing palate, but not in the tongue. Consequently, an ectopic Wnt/β-catenin signaling activity is found in the Gsk3β−/− tongue, but not in the Gsk3β−/− palate. These observations suggest a redundant role for Gsk3β and Gsk3α during palate development. The absence of Gsk3β does not alter the Wnt/β-catenin signaling, suggesting that Gsk3β could also mediate a signaling pathway independent of Wnt/β-catenin signaling during palate development.
Generation and Genotyping of Gsk3β Conditional Knockout Mice
Targeting construct for Gsk3β was created using a recombineering strategy (Liu et al.,2003). Briefly, a bacterial artificial chromosome (BAC) clone containing the murine Gsk3β locus, from Children's Hospital of Oakland Research Institute (CHORI), was transformed into EL350 cells. Polymerase chain reaction (PCR) was used to retrieve approximately 400-bp homology arms flanking exon 2 of Gsk3β by 5-kb on each side. Deletion of this exon has been shown to result in a nonfunctional kinase (Hoeflich et al.,2000). After cloning homology arms into a retrieval vector (pBluescript modified to contain a thymidine kinase [TK] cassette), this construct was transformed into the EL350 BAC-containing cells, and induced homologous recombination by means of gap repair, resulting in a 10-kb fragment of Gsk3β being retrieved into the pBluescript derivative. Next, mini-targeting vectors were created by introducing identical 34-bp loxP sites on both sides of a neomycin resistance cassette (neomycin phosphotransferase gene; NeoR). The loxP/NeoR cassette was then introduced into gap repaired retrieval plasmids using a similar approach as just described above for retrieving the Gsk3β fragment. Transformation of these constructs into bacteria with arabinose-inducible Cre allowed recombination, removing the NeoR cassette and one loxP site. An additional round of this cloning approach was used to introduce a second loxP/NeoR cassette, now flanked by FRT sites, on the 3′ side of exon 2. Plasmids were linearized with NotI, gel purified, and electroporated into mouse ES cells by the ES Cell and Transgenic Core Facility at The Research Institute at Nationwide Children's Hospital. Targeted ES cells were grown in the presence of G418 (350 μg/ml) and FIAU (5-iodo-2′-fluoro-2′-deoxy-arabinouridine; 200 nM) for the selection of cells which contained correct gene targeting.
Southern blotting of G418/FIAU-resistant clones revealed 11 of 288 colonies (3.8%) contained a correctly targeted Gsk3β floxed allele. Two clones were selected for injection into blastocysts, from which we obtained several male chimeric mice. These mice were mated to either ROSA26-FLPe mice, a well-characterized transgenic mouse that ubiquitously expresses Flp at high levels (Farley et al.,2000) resulting in the highly efficient removal of the NeoR cassette, or wild-type C57BL/6 females. Primer information for PCR genotyping is available upon request.
Other Animals
The conventional Gsk3β mutant (Gsk3β+/−) mice were generated by intercrossing Gsk3β conditional (Gsk3βF/F) mice with the Sox2Cre transgenic mice. Sox2Cre and TOPGAL mice were obtained from the Jackson Laboratories (Bar Harbor, ME) and were genotyped as described previously (DasGupta and Fuchs,1999; Hayashi et al.,2002). The generation and genotyping of Pitx2Cre and Osr2Cre transgenic mice have been reported previously (Lan et al.,2007; Xiong et al.,2009). All the genetically engineered mice used in this study were maintained on the B6/C57 background. The age of embryos was defined as embryonic day 0.5 (E0.5) in the morning of the day when a vaginal plug was discovered. All animal studies were approved by the Tulane University Institutional Animal Care and Use Committee.
In Vitro Organ Culture
E13.5 embryos were harvested from Gsk3β+/− crosses and decapitated. After removal of mandible, each embryonic head was placed in 2 ml DMEM culture medium supplemented with 20% fetal calf serum in a 20-ml glass bottle. Bottles were fixed in vertical position on a rotary apparatus rotating at a speed of 4 rpm in an incubator at 37°C and 5% CO2. Samples were harvested after 24 hr in culture, and processed for histological examination.
Histology and In Situ Hybridization
Staged embryos were harvested in ice-cold phosphate buffered saline (PBS), and embryonic heads were removed and fixed in 4% paraformaldehyde (PFA)/PBS overnight at 4°C before dehydration through a graded ethanol series and embedded in paraffin. Samples were processed into 10-μm coronal sections for histological analysis by standard hematoxylin/eosin staining or for nonradioactive in situ hybridization, as described previously (St. Amand et al.,2000). For the expression of each gene, three independent experiments of in situ hybridization were performed.
X-gal Staining
Embryos were collected, and embryonic heads were dissected in ice-cold PBS. The mandible of each head was carefully removed with a pair of fine forceps and discarded. Samples were washed in PBS, and fixed in 1% glutaraldehyde/PBS at 4°C for 1 hr. After three washes in PBS, samples were stained in X-gal solution (400 μg/ml, with potassium ferricyanide and potassium ferrocyanide) overnight at room temperature for β-galactosidase activity.
Cell Proliferation and TUNEL Assays
Cell proliferation rate was measured using the Bromodeoxyuridine (BrdU) Labeling and Detection Kit (Roche Diagnostics Corporation, Indianapolis). Briefly, timed pregnant female mice were injected intraperitoneally with BrdU solution (1.5 ml/100 g body weight) 1 hr before embryos were harvested. Embryonic heads were fixed in Carnoy's fixative, dehydrated, embedded in paraffin, and sectioned at 5 μm for immunostaining according to manufacturer's instruction (He et al.,2008). BrdU-labeled cells were counted within arbitrarily defined areas and presented as percentage of total nuclei of the same area. With data collected from nine sections of three individual samples of wild-type controls and mutants, respectively, were subjected to Student's t-test to determine the significance of differences. For TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridinetriphosphate nick end-labeling) assays, samples were fixed in 4% PFA/PBS, dehydrated, and embedded in paraffin. Coronal sections were made at 5 μm thickness. Apoptotic cells were detected as described previously (Alappat et al., 2005).
We thank Dr. Hao Ding of University of Manitoba, Canada and Dr. Andras Nagy of Mount Sinai Hospital, Canada, for providing Pdgfa and Pdgfc probes. We thank Dr. Rulang Jiang of the University of Rochester for providing Osr2-Cre mice. C.J.P. and Y.C. were funded by the NIH.
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- 2003. Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development 130: 1003–1015. , , , .
- 2002. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 129: 4135–4146. , , , , , .


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To what extent are they sweat-proof?
If I ran using the earbuds that came with my iPhone4, they did not function properly after I'd run a few miles - presuming that had to do with the amount of sweat.. that is, the playback would speed up (such that it sounded like chipmunks were singing), or it might randomly skip ahead to the next song while the first was playing, etc. This didn't happen when I switched to a non-apple set of earbuds, but it's recurred when I've used the original earbuds. I know they're not meant to be water-proof per se, but would like to have some assurance of that they'd still function properly while I exercise, too.
- Asked by Marla S from Rockville
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Gym and sweat for upto 9 hours a day even wont affect these
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Are these sweat proof ? To wear to the gym or while running ?
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is this water proof
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Are these good for exercising? In other words, are they sweat-proof?
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Hayday Farm Game
If you searching for Hayday Farm Game, you come to the right place. Here you can read or download Hayday Farm Game directly from the official website. Free download APK file for your Android device. This android applications, android games, android themes, android how to troubleshooting or android apk is provided by the community, and you will read or download from their server.
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We are currently recruiting for the Spring and Summer sessions of 2017. As Grande continues to grow our Engineering Co-op and Intern programs, we are looking...
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zSpace, Inc. - Sunnyvale, CA
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text:
I have never read any of Eddings works.
So my question is: "With which one should I start?"
I have heard that the "Garion" tales are considered superior because the "Sparhawk" and "Dreamer" works are considered so derivative-- but if I have never read either, which one might I find to be more satisfactory?
Because the plots are apparently so similar-- I expect, that, for me at least, reading the second or third one could be a bit of a letdown after reading the first one I ever read.
Is Elen/Tam or Dreamers really a second-rate rehash, or is one of them the pennicle of refining an art?
Is any single series superior to another in any respect?
Is any one of the sagas less violent than either of the others? Is any one particularly better suited to read with younger readers? (My son is only five years old now, but if I like these tales I might want to encourage him to read my favorite series.)
I know I should probably read them all and then decide which one I like the best, but I really think I would tire of derivative characters or plots and hold a fondness for the one I experienced first.
Any suggestions?
Recent discussions in the david eddings forum (1 discussion)
|Latest Post
|Never Read Eddings; Where to Start?
|Jan 23, 2008


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MIAMI (CBSMiami) — The FBI is searching for a man accused of robbing a Coral Gables bank Friday afternoon.
The agency release picture of the robbery which took place at 3:00 p.m. at the Chase Bank branch located at , 1300 Ponce De Leon Boulevard.
Detectives said the robber entered the bank and demanded money from a bank employee.
Customers were in the bank at the time of the robbery.
There were no injuries.
The robber did get away with money but it is not clear how much.
Anyone with information is urged to call Miami-Dade Crimestoppers at 305- 471-TIPS.
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Erin Cardillo - Friday 15th June 2007 at Daytime Emmy Awards Hollywood, California (3 Pictures)
Erin Cardillo
Photo credit: (Mandatory): Starbux / WENN
Erin Cardillo
Photo credit: (Mandatory): Nikki Nelson / WENN
Erin Cardillo
Photo credit: (Mandatory): Nikki Nelson / WENN
View All: Erin Cardillo - Friday 15th June 2007...
Next Erin Cardillo Slideshow: SOAPnet's "Night Before Party" for 2007 Daytime Emmy Award Nominees held at Boulevard 3 - Arrivals - Hollywood, California - Thursday 14th June 2007
Perry performed 'Rise' and 'Roar' before Clinton accepted the nomination to be the Democrats' presidential candidate.
Bruce Springsteen will release rare tracks from 1966 in new album 'Chapter and Verse', which will accompany his autobiography 'Born To Run'.
There's still no reunion planned though.
Not broadcast in its entirety since 1967, a full restoration will be played in select cinemas to support Ron Howard's 'Eight Days a Week' touring...


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Crazy Substitute Teachers
Enjoy, NG4.03 / 5.00 2,599 Views
Vacuum Salesman
This dude and his Megazord vacuum cleaner4.02 / 5.00 2,877 Views
Markiplier Animated | Mark Of The Survey Corps
This took far too long to make...3.96 / 5.00 7,305 Views
2 words: UBER EPIC!
That was awesome!
this is a easy infinate stars it is amazing it is beast.
guys part 9 is out on youtube.com
You dont know how many tmes i have wanted to hit an Enderman in the balls. Thank you for doing that lol
Great stuff Btw


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Talk about getting cold feet! Brooke Shields steps out in SANDALS on a very chilly day in the Big Apple
The temperatures in New York are hovering around the zero mark but one person who seems underprepared for the cold snap is Brooke Shields.
The actress must have had freezing feet when she stepped out on Saturday as she made the very bad decision of wearing sandals.
The 47-year-old seemed to be grimacing from the chilly weather as she strolled down the street with a friend.
What was she thinking?: Brooke Shields stepped out in sandals in New York on Saturday despite the cold weather
But when she clocked photographers Brooke gave a smile and even made a peace sign.
Fortunately, the Blue Lagoon star had been a little more sensible when it came to the rest of her outfit.
She kept most of her body warm with a thick padded coat that also boasted a fur-trimmed hood, and covered her legs with jeans.
At least she has a sunny attitude: The actress gave a smile and made a peace sign at photographers
Saving grace: Thankfully the 47-year-old had chosen a thick coat for her outing with a pal
Brooke and her family have
been gearing up for Christmas and last week the brunette beauty took
her two daughters to see Santa Claus.
and her brood appear to be looking forward to the holiday but sadly
will miss the presence of Brooke's mother and former manager Teri, who
died last month aged 79.
Brooke released a heartfelt statement to People magazine at the time.
That's better! On Sunday Brooke Shields covered up her toes as she headed out with friends in New York
The former flame of Michael Jackson, who had a troubled relationship with Teri who masterminded her daughter's career after launching her into showbiz as a baby, said she wouldn't be who she was today if it wasn't for her mother.
'My mother was an enormous part of my life and of who I am today,' Brooke said.
'I loved her, laughed with her, and respected her. And although she had her share of struggles, she was my mom.'
Doting mum: Brooke shields poses with her daughters Rowan and Grier
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