, 2006). Instead, IPCs in Robo1/2 mutants divide much slower than normal, which eventually leads

to a relatively normal rate of neuronal production. It is conceivable that this phenotype might be secondary to the failure of IPCs to retract their apical process from the VZ. Indeed, an exploratory analysis of the organization of adherens junctions in Robo1/2 mutants revealed abnormal levels of some proteins, most prominently N-Cadherin ( Figure S9). AT13387 datasheet This idea is consistent with previous results demonstrating that Robo signaling inhibits cadherin-based adhesions in other cellular contexts ( Rhee et al., 2002; Wong et al., 2012; Zhou et al., 2011). Our results are in sharp contrast with previous work suggesting that loss of Slit/Robo signaling leads to an increase in the number of mitosis in the VZ of the subpallium (Andrews et al., 2008). Other than possible differences in strain backgrounds or methodological considerations, we cannot explain the origin of this discrepancy. Our analysis reveals small but consistent deficits in VZ mitosis throughout the CNS, indicating that this phenotype is not restricted to a particular brain region. Based on the increased number of IPCs in Robo mutants, we interpreted the reduced number of VZ mitosis as

a premature shift from symmetric to asymmetric cell BMS-354825 molecular weight divisions. This would suggest that Slit/Robo signaling might be mostly involved in controlling the mode of cell division in neural progenitors and not so much their rate. This interpretation is consistent with previous work in Drosophila, in which loss of Slit has been shown to modify Oxalosuccinic acid the pattern of cell division for specific neural lineages ( Mehta and Bhat, 2001). It is also worth mentioning that Robo2 levels have been reported to decrease in the cortex of E13.5 mouse mutants

for insulinoma-associated 1, a panneurogenic gene that regulates the balance between apical and basal progenitors in the developing cortex ( Farkas et al., 2008). This process also seems regulated by FGF signaling, because Fgfr1/2/3 triple mutant mice also exhibited a loss of apical progenitors and an increase of Tbr2+ basal progenitors ( Kang et al., 2009). Although Robo signaling has been classically linked to the cytoskeleton (Bashaw et al., 2000; Hu et al., 2005; Rhee et al., 2002; Wong et al., 2001; Yang and Bashaw, 2006), the unexpected function of Robo receptors in neural progenitor cells prompted us to explore alternative signaling pathways. Intriguingly, Robo function in progenitor cells appears to be mediated, at least in part, by transcriptional regulation. Previous studies have proposed that Robo signaling might modulate transcription in other cellular contexts (Grieshammer et al., 2004; Rhee et al., 2007), although no direct targets were identified.