estradiol is a neuroactive steroid that exerts hormonal as well as local paracrine or autocrine actions in the central nervous system , during development and in adulthood . estradiol is produced in the ovary and in other tissues by the enzyme aromatase , which , in the brain , is expressed by specific neuronal populations ( roselli et al . for instance , aromatase is expressed by neural progenitor cells in vertebrates ( mouriec et al . , 2008 ) and it is involved in the regulation of neural progenitor cell proliferation in the embryonic cerebral cortex of mice ( martinez - cerdeno et al . , in addition , many of the developmental effects of hormonal testosterone on male brain sexual differentiation are mediated by its local conversion to estradiol by neurons expressing the enzyme aromatase ( maclusky and naftolin , 1981 ; roselli et al . , 2009 ) . furthermore , recent evidence indicate that estradiol also participates in the regulation of brain sexual differentiation in females ( bakker and brock , 2010 ; brock et al . , 2011 ) . in addition to regulate the proliferation of neural progenitor cells ( martinez - cerdeno et al . , 2006 ) , estradiol modulates the development of postmitotic neurons , affecting the growth of axons , dendrites and dendritic spines , and the formation of synapses ( ferreira and caceres , 1991 ; daz et al . , 1992 ; duenas et al . , 1996 ; beyer and karolczak , 2000 ; woolley , 2000 ; blacklock et al . , 2005 ; tsutsui , 2006 ; miano et al . , 2008 ; bender et al . , these developmental actions depend in many cases of local estradiol synthesis ( kretz et al . , 2004 ; , 2006 ; hu et al . , 2007 ; sasahara et al . , 2007 ) . the activation of notch by transmembrane ligands , delta - like , and jagged , results in the cleavage of the molecule and the release of a notch intracellular domain that is translocated to the cell nucleus and regulates transcriptional activity ( lai , 2004 ) . notch signaling controls cell - fate specification , differentiation , proliferation , and apoptosis in developing tissues ( artavanis - tsakonas et al . , 1999 ) . in the nervous system , notch signaling regulates neurogenesis and gliogenesis , not only during development but also in the adult brain ( louvi and artavanis - tsakonas , 2006 ; ables et al . , 2011 ; pierfelice et al . , in contrast , the inhibition of notch signaling promotes neurite extension ( berezovska et al . , 1999 ; the activation of notch signaling in developing hippocampal neurons in vitro ( figure 1 ) is associated with an increase in the expression of the transcription factors hairy and enhancer of split ( he s ) 1 and 5 ( salama - cohen et al . , 2005 ) . one of such genes is the basic helix - loop - helix transcription factor neurogenin 3 ( ngn3 ) , which in developing pancreas is a proendocrine gene that causes the differentiation of the four endocrine cell lineages ( lee et al . , 2001 ; rukstalis and habener , 2009 ) and that it is downregulated by notch signaling via hes1 ( lee et al . , 2001 ) . activation of notch signaling in neurons also induces a decrease in the expression of ngn3 ( salama - cohen et al . , ngn3 participates in different developmental events in the central nervous system . in the developing spinal cord , ngn3 is expressed in glial precursor cells and it is necessary for the normal differentiation of mature oligodendrocytes and astrocytes ( lee et al . , 2003 ) . in chick embryos , ngn3 promotes early retinal neurogenesis ( ma et al . , 2009 ) . in the hypothalamus , ngn3 regulates the differentiation of several neuronal populations , including proopiomelanocortin ( pomc ) and neuropetide y ( npy ) neurons , which play a central role in energy balance and the control of food intake ( pelling et al . , 2011 ) . in hippocampal neurons , ngn3 promotes the growth of dendrites and regulates the number of afferent gabaergic synaptic inputs ( salama - cohen et al . , 2006 ) . therefore , the activation of notch in developing hippocampal neurons represses the process of dendritogenesis by the downregulation of ngn3 ( figure 1 ) . notch signaling represses dendritogenesis in developing hippocampal neurons by downregulating the expression of neurogenin 3 . the binding of notch ligands ( delta - like , jagged ) results in the cleavage of notch and the release of an active intracellular domain that is translocated to the cell nucleus where it enhances the transcription of target genes , such as hes1 , that repress the transcription of ngn3 . cross - talk between estradiol and notch signaling has been detected in breast cancer cells and endothelial cells ( soares et al . , 2004 ; sobrino et al . , furthermore , the estrogenic compound genistein downregulates notch-1 in prostate cancer cells ( wang et al . in breast cancer cells , estradiol decreases notch transcriptional activity via an estrogen receptor ( er ) -mediated inhibition of notch cleavage by -secretase ( rizzo et al . , 2008 ) . in turn , notch-1 activates er-dependent transcription in these cells in the presence or absence of estradiol ( hao et al . , therefore , estradiol regulates notch signaling and notch signaling regulates estrogen signaling in breast cancer cells . it remains to be determined whether the cross - regulation of estrogen and notch signaling also occurs in other cell types . given the importance of notch signaling for brain development , it is important to explore whether such interaction takes place in neural cells . recent studies have shown that estradiol reduces the levels of the intracellular transcriptionally active domain of notch-1 in hippocampal slice cultures ( bender et al . , 2010 ) . this suggests that estradiol may decrease notch-1 mediated transcription in hippocampal cells by reducing notch-1 cleavage ( figure 2 ) . in primary cultures of mice hippocampal neurons , estradiol decreases the expression of hes1 and increases the expression of ngn3 ( ruiz - palmero et al . , 2011 ) . these findings further indicate that estradiol downregulates notch signaling in hippocampal neurons ( figure 2 ) . the effect of estradiol is not imitated by er or er agonists and it is not blocked by er or er antagonists . in contrast , g1 , agonist of the putative membrane estrogen receptor gpr30 , imitate the effect of estradiol on ngn3 expression and dendritogenesis , suggesting that the action of estradiol is mediated by gpr30 . g protein - coupled receptor 30 ( gpr30 ) , also known as g protein - coupled estrogen receptor ( gper ) , is a putative membrane associated er ( prossnitz et al . , 2008 ; olde and leeb - lundberg , 2009 ; prossnitz and maggiolini , 2009 ; langer et al . , 2010 ) . gpr30 seems to be involved in the regulation of notch signaling in hippocampal neurons , since g1 , a ligand of gpr30 that imitates the effects of estradiol in different cell types and tissues ( terasawa et al . , 2009 ; zhang et al . , 2010 ) also imitates the effect of estradiol on ngn3 expression in hippocampal neurons ( ruiz - palmero et al . , 2011 ) . in contrast , neither the er agonist 4,4,4-(4-propyl-[1h]-pyrazole-1,3,5-triyl ) trisphenol ( ppt ) nor the er agonist 2,3-bis ( 4-hydroxyphenyl)-propionitrile ( dpn ) affect the expression of ngn3 in hippocampal neurons ( ruiz - palmero et al . , 2011 ) . in addition , 1,3-bis ( 4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy ) phenol]-1h - pyrazole ( mpp ) and 4-[2-phenyl-5,7-bis ( trifluoromethyl ) pyrazolo [ 1,5-a ] pyrimidin-3-yl ] phenol ( phtpp ) , selective antagonists of er and er mediated transcription , respectively , do not antagonize the effect of estradiol on ngn3 expression ( ruiz - palmero et al . , 2011 ) . furthermore , ici 182,780 ( ici ) , antagonist of both er and er mediated transcription and agonist of gpr30 ( thomas et al . , 2005 ) , not only does not block , but even imitates , the effect of estradiol on ngn3 expression ( ruiz - palmero et al . , 2011 ) . therefore , estradiol may regulate ngn3 levels in hippocampal neurons by a non - canonical mechanism , which probably is independent of classical nuclear er mediated transcription . the neuritogenic action of estradiol is mediated by the activation of the mitogen activated protein kinase ( mapk ) cascade among other signaling mechanisms ( carrer et al . , 2003 , 2005 ; dominguez et al . , 2004 ; gorosito and cambiasso , 2008 ; miano et al . , 2008 ) . recent studies have assessed whether notch signaling is also involved in the neuritogenic actions of estradiol . estradiol promotes dendritogenesis in primary hippocampal neurons in culture ; this effect is imitated by g1 and it is not blocked by ici ( ruiz - palmero et al . , 2011 ) . furthermore , neither g1 nor estradiol promote dendritogenesis in hippocampal neurons when ngn3 is downregulated using ngn3-specific sirna oligonucleotides ( ruiz - palmero et al . , 2011 ) . therefore estradiol and g1 may act through common mechanisms to regulate ngn3 expression and dendritogenesis by the inhibition of notch signaling ( figure 2 ) . the studies reviewed here indicate that estradiol interacts with notch signaling in the nervous system . estradiol regulates dendritogenesis in developing hippocampal neurons through the modulation of notch signaling and the upregulation of ngn3 by a mechanism involving the putative membrane er gpr30 . further studies are necessary to determine whether this mechanism also operates in other neuronal types . in addition , new experiments are needed to clarify the molecular mechanisms linking estrogen / gpr30 and notch signaling in neurons . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
the transmembrane receptor notch , a master developmental regulator , controls gliogenesis , neurogenesis , and neurite development in the nervous system . 
 estradiol , acting as a hormonal signal or as a neurosteroid , also regulates these developmental processes . 
 here we review recent evidence indicating that estradiol and notch signaling interact in developing hippocampal neurons by a mechanism involving the putative membrane receptor g protein - coupled receptor 30 . 
 this interaction is relevant for the control of neuronal differentiation , since the downregulation of notch signaling by estradiol results in the upregulation of neurogenin 3 , which in turn promotes dendritogenesis .