been indicated in several reports. Mutations in elements of the Notch signaling pathway affect the earliest intestinal cell fate decisions during zebrafish development. Transcriptional analysis and gain of function experiments revealed that Notch signaling targets Hes1 in the intestine and regulates a binary cell fate decision between adsorptive and secretory cell fates. Bone development Early in vitro studies have found the Notch signaling pathway functions as down-regulator in osteoclastogenesis and osteoblastogenesis. Notch1 is expressed in the mesenchymal condensation area and subsequently in the hypertrophic chondrocytes during chondrogenesis. Overexpression of Notch signaling inhibits bone morphogenetic protein2-induced osteoblast differentiation. Overall, Notch signaling has a major role in the commitment of mesenchymal cells to the osteoblastic lineage and provides a possible therapeutic approach to bone regeneration. Role in cancer Leukemia Aberrant Notch signaling is a driver of T cell acute lymphoblastic leukemia (T-ALL) and is mutated in at least 65% of all T-ALL cases. Notch signaling can be activated by mutations in Notch itself, inactivating mutations in FBXW7 (a negative regulator of Notch1), or rarely by t(7;9)(q34;q34.3) translocation. In the context of T-ALL, Notch activity cooperates with additional oncogenic lesions such as c-MYC to activate anabolic pathways such as ribosome and protein biosynthesis thereby promoting leukemia cell growth. Urothelial bladder cancer Loss of Notch activity is a driving event in urothelial cancer. A study identified inactivating mutations in components of the Notch pathway in over 40% of examined human bladder carcinomas. In mouse models, genetic inactivation of Notch signaling results in Erk1/2 phosphorylation leading to tumorigenesis in the urinary tract. As not all NOTCH receptors are equally involved in the urothelial bladder cancer, 90% of samples in one study had some level of NOTCH3 expression, suggesting that NOTCH3 plays an important role in urothelial bladder cancer. A higher level of NOTCH3 expression was observed in high-grade tumors, and a higher level of positivity was associated with a higher mortality risk. NOTCH3 was identified as an independent predictor of poor outcome. Therefore, it is suggested that NOTCH3 could be used as a marker for urothelial bladder cancer-specific mortality risk. It was also shown that NOTCH3 expression could be a prognostic immunohistochemical marker for clinical follow-up of urothelial bladder cancer patients, contributing to a more individualized approach by selecting patients to undergo control cystoscopy after a shorter time interval. Notch inhibitors The involvement of Notch signaling in many cancers has led to investigation of notch