The next step will be to identify the molecular mechanisms through which this signaling heterogeneity

is achieved. The general roles of Notch signaling in embryonic neural progenitors, and in the canonical signal transduction cascade, are well established. The primary known targets with respect to neural buy MI-773 development in mammals are Hes1 and Hes5. Interestingly, while Hes1 can certainly be regulated by Notch signaling, it also appears to receive regulatory inputs from a number of other signaling cascades, including those of the Sonic Hedgehog (Shh) (Ingram et al., 2008, Solecki et al., 2001 and Wall et al., 2009) and JAK/STAT pathways (Bhattacharya et al., 2008, Kamakura et al., 2004 and Yoshimatsu et al., 2006). As Hes1 can inhibit neuronal differentiation, having multiple input mechanisms to drive its expression could provide redundancy and/or pathway connectivity. Although a role for oscillatory Hes1 expression has been known for many years with respect to somitogenesis (Aulehla and Pourquié, 2008), only recently has such an oscillatory pattern been observed in the embryonic nervous system (Kageyama et al., 2008b and Shimojo et al., 2008). The static nature of most developmental studies, especially in mice, VX-770 clinical trial has resulted in snapshots of development

that have led to assumptions regarding the dynamics of gene expression. The model in neocortical development, for example, has been that competition between adjacent cells in the VZ leads to certain cells expressing high levels of Notch SB-3CT targets, including Hes1,

while other cells express lower levels of Hes1, and instead express proneural genes (e.g., Neurog2) and the Notch ligands they regulate (Castro et al., 2006 and Nelson et al., 2009). However, this modeling typically invokes stochastic fluctuations in gene expression as playing a part in generating heterogeneity, such that initial slight differences are then amplified via reinforcing feedback loops. The autoregulatory function of Hes1, which can repress its own expression (Hirata et al., 2002), lends itself well to driving fluctuations in gene expression such that adjacent cells would have differential expressions, which could then be amplified. Oscillatory expression of Hes1, and consequently other elements of the pathway (Shimojo et al., 2008), would create a “pulsatile” inhibition of neurogenesis, whereby only after fixing Hes1 expression in the low/off position, could neuronal differentiation proceed (Figure 3). Shimojo and colleagues found the oscillation cycle of Hes1 in neural progenitors to be about 2 hr, consistent with what has been observed in other settings (Hirata et al., 2002 and Kobayashi et al., 2009).