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5 stage. Regarding the endocrine competence dynamics (beta-cell formation), a similar argument can be posited. Using explant studies, we observed the emergence of pancreatic beta cells from Ngn3 Delayed-ON pancreas, upon providing DAPT after the TrPC patterning effect of the transgene had been established. One possibility explaining endocrine gestational dependency is that beta-cell competence is related to TrPC formation and that this is at least partially explained through Notch activation of Nkx6.1. It is well known that Nkx6.1 is critical for beta cell function in the adult state and it is also involved in beta cell formation during embryonic stages. Relevant questions emerge such as how Nkx6.1 presence may impact the alpha/beta cell subtype switch that is controlled by relative Pax4/Arx expression? Also, [http://www.selleckchem.com/products/lonafarnib-sch66336.html Lonafarnib cell line] could Notch/Hes1 be involved in controlling the Pax4/Arx dynamics in a more direct [http://en.wikipedia.org/wiki/VAV2 VAV2] manner? While our data does not specifically address the importance of duration of Notch signaling it is possible that Notch-mediated epigenetic changes, accumulating over time, could be involved development of beta cell competence, and that such would be propagated from TrPC determinant loci, including Nkx6.1. If so, the prolongation of Notch activation, rather than total level of induction, could be critical. Some of these emerging opportunities might influence the differentiation strategies of pluripotent cells towards the beta cell fate. We uncovered a novel post-transcriptional involvement of Notch signaling negatively controlling Ngn3 protein. The current basis for understanding lateral inhibition in pancreas, as well as elsewhere, largely centers on cross-repressive transcriptional control. Transcriptional repressive systems are known in somitogenesis, as well as neurogenesis, and the current paradigm is that Notch-driven Hes-class protein production leading to repression of transcription of various lineage-specific bHLH genes, such as Ngn3 in pancreas ( Lee et al., 2001). For instance, in the Ngn3 Delayed ON model, there is an almost complete abrogation of expression of endogenous Ngn3 mRNA, as would be expected through transcriptional repression of Ngn3 by Hes1 ( Fig. 4H). In addition, we now uncover that Notch-controlled proteolysis of Ngn3 also occurs. Similar results have been described for Notch-induced [http://www.selleckchem.com/screening/tyrosine-kinase-inhibitor-library.html Selleckchem Tyrosine Kinase Inhibitor Library] ubiquitination and degradation of hASH1 ( Sriuranpong et al., 2002), E2A ( Nie et al., 2003), and TAL/SCL ( Nie et al., 2008). These bHLH factors have demonstrated half-lives