We found that Robo receptors

We found that Robo receptors BI 2536 mouse maintain cortical progenitor balance through interaction with the Notch pathway by controlling Hes1 transcription. Our study uncovers a novel role for Slit/Robo signaling in progenitor cells, which expands the vast repertoire of biological functions already attributed to this highly conserved pathway. We have previously reported that Robo1/2 mutants are essential

for the development of major axonal projections in the mouse-developing forebrain ( López-Bendito et al., 2007). As part of this analysis, we found that the brain of Robo1/2 mutants is smaller than controls at birth ( Figure 1A). For example, the volume of the telencephalon and thalamus in Robo1/2 mutants was consistently smaller than controls as early as E14.5 ( Figures 1C–1G; data not shown). The thickness of the neocortex was also significantly reduced in Robo1/2 mutants compared to controls ( Figures 1D, 1F, and 1G). Despite this difference, layer formation in the developing cortex seems to proceed normally ( Figures 1B and S1 available online). We reasoned that the prominent axon guidance defects that exist in Robo1/2 mutants could explain part of the size differences observed in our analyses ( López-Bendito et al., 2007). However, we also noticed that the cortical germinal epithelium of Robo1/2 mutants was much thinner than that of control brains at birth (red brackets

in Figures 1B, 1D, and 1F). Since these defects could not be simply explained selleck chemicals llc by defective axons, this finding prompted us to study a possible role of Robo signaling in neural progenitors. To assess a possible role for Robo receptors in neural precursor cells,

we first examined the expression of Robo1 and Robo2 messenger RNA (mRNA) in progenitor regions throughout the developing CNS. We found that Robo1 and Robo2 are expressed in most progenitor epithelia in the developing forebrain (E12.5) and spinal cord (E9.5) (red asterisks in Figures MTMR9 2A–2F), although different regions predominantly express one of the receptors. For example, progenitor cells in the VZ of the developing pallium express relatively high Robo2 mRNA levels ( Figures 2C, 2D, and S2A–S2J), while Robo1 is more abundantly expressed in the VZ of the medial and lateral ganglionic eminences (MGE and LGE, respectively; Figures 2C, 2D, and S2A–S2J). Consistently, immunohistochemical experiments revealed expression of Robo2 in the VZ of the cortex with barely detectable levels of Robo1 ( Figures 2G and 2J). Nevertheless, semiquantitative RT-PCR and western blot analyses in tissue obtained from the cortex of E10.5 embryos revealed expression of both receptors ( Figures S2K and S2L). These results confirmed the presence of Robo1 and Robo2 in progenitor cells, because the mouse cerebral cortex is almost entirely devoid of neurons at this early stage. We also discovered that the expression of Robo receptors in progenitor regions followed a very dynamic pattern.

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