, 2005 and Ge et al., 2002), and the newly identified Nepro, which appears to act downstream of Notch to inhibit neurogenesis early ERK inhibitor ic50 in neocortical development (Muroyama and Saito, 2009). Though direct lateral inhibition is a
well-established model, in many instances, it more than likely cannot account for refining the Delta-Notch signaling pattern during development. Interestingly, it was reported in Drosophila neural development that dynamic filopodia can contact nonneighboring cells, allowing intermittent Delta-Notch signaling to regulate bristle spacing and organization ( Cohen et al., 2010). Such filopodia provide a means for individual cells to influence cohorts of nearby cells, and could permit integration of broader signaling trends across a tissue, rather than have everything be
determined on a neighboring cell-by-cell basis. Though such filopodial Notch signaling has yet to be observed in other organisms, it will be important to determine whether vertebrate NSCs use a similar means of intermittent Notch-Delta signaling, and how such a cellular mechanism could be employed to regulate and refine neural cell fate specification. In addition to the core signaling elements, Notch pathway modulators have been characterized to varying extents, including Numb (Zhong et al., 1996), Numblike (Numbl) (Zhong et al., 1997), and Dx (Eiraku et al., 2005, Patten et al., 2006, Sestan et al., 1999 and Yamamoto et al., 2001). Unfortunately, after many years of study, how these components regulate the Notch cascade in the developing mammalian nervous Z-VAD-FMK concentration system is not entirely clear. Numb and Numblike can antagonize Notch signaling (Sestan et al., 1999 and Shen et al., 2002), but disruption of these proteins in mice has not been easily reconciled with such
a function, because Terminal deoxynucleotidyl transferase some studies have suggested that Numb promotes progenitor character, while others suggest it promotes neurogenesis (Li et al., 2003, Petersen et al., 2002, Petersen et al., 2004, Petersen et al., 2006 and Rasin et al., 2007). Recent work has provided potential insight into the regulation of Numb by the Golgi-associated protein ACBD3 (Zhou et al., 2007). The model presented suggests that during mitosis and Golgi fragmentation, ACBD3 is released into the cytosol where it can interact with asymmetrically localized Numb to promote progenitor character in the daughter cell that contains Numb. However, once newly generated neurons become postmitotic, ACBD3 is retained in the Golgi, and Numb/Numbl instead antagonize Notch to permit neuronal maturation. The importance of regulating Notch signaling in differentiating neurons is supported by studies that found that Notch can influence dendritic arborization (see below) (Berezovska et al., 1999, Redmond et al., 2000 and Sestan et al., 1999) and axonal guidance (Giniger, 1998, Le Gall et al., 2008 and Song and Giniger, 2011).