Ptch1-mediated dosage-dependent action of Shh signaling regulates neural progenitor development at late gestational stages

Abstract

Sonic hedgehog (Shh) signaling regulates cell differentiation and proliferation during brain development. However, the role of Shh in neurogenesis during late gestation (embryonic day 13.5-18.5) remains unclear. Herein, we used a genetic approach and in utero electroporation to investigate the role of mouse Shh and patched homolog 1 (Ptch1), the putative receptor for Shh. Proliferating cortical intermediate (basal) progenitor cells (IPCs) were severely reduced in Shh mutant mice, suggesting that endogenous Shh signaling could play an essential role in cortical IPC development. During cortical neurogenesis, strong upregulation of Shh signaling enhanced the transition from ventricular zone (VZ) progenitors to ventralized IPCs, while low levels of signaling enhanced the generation and proliferation of cortical IPCs in the subventricular zone. The effects of Shh upregulation in this study were consistent with a phenotype of conditional loss of function of Ptch1, and the phenotype of a hypomorphic allele of Ptch1, respectively. These data indicated that endogenous Ptch1 mediates the broad effects of Shh on the transition from VZ progenitors to IPCs and activation of proliferation of the IPCs in the cortex during late gestational stages.

Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/ß-catenin signaling

“…In order to achieve the increase in population size that we observe in our lineage analysis, radial glia must undergo amplifying self-renewing divisions, and, as has been shown in the telencephalon (Barbosa et al, 2015), regeneration may require these divisions at an even higher frequency. However, our data indicate that ectopic Wnt activity in fact inhibits expansion of the hypothalamic radial glia population, while other studies suggest that signals such as FGF (Kaslin et al, 2009;Robins et al, 2013) and Sonic hedgehog (Dave et al, 2011;Shikata et al, 2011;Komada, 2012) are likely to promote this process. We found that a specific subset of lef1-dependent neurons located near the hypothalamic ventricle arise from the radial glial lineage .…”

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

“…Similar to what we discussed for Notch signaling and possibly also for FGF signaling, Shh signaling shows dosage-dependent effects, intercepts both caNotch and noncaNotch signaling pathway branches (e.g., Hes5 and Hes3) (5,112), and NSC biology may contribute to our understanding of Shh regulation in the pancreas.…”

“…In neural development, different levels of Shh result in different cellular outcomes, with low Shh levels more prone to promoting self-renewal/proliferation and high Shh more prone to morphogenetic/cell specification decisions (112). The dosage-dependent Shh effects may be linked to the dosage-dependent Notch effects.…”

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development

“…Shikata and colleagues used in utero electroporation to overexpress varying levels of Shh beginning at E13.5 and found differential effects on cortical development [49]. In areas with low to moderate levels of Shh overexpression (fewer than 20 cells transfected with Shh expression vector), significant increases in Tbr2+ IPs were evident.…”

“…Removal of Ptch1 in Nestin+cortical progenitors at E11.5 resulted in extensive folding and decreased cortical thickness due to an increase in symmetrically dividing RG cells, at the expense of neurogenic division, thereby reducing IP cell production [34]. On the other hand, inactivation of Ptch1 in the neocortex of the E17-E18 mouse abolished RG self-renewal, indicating enhanced transition of RG progenitors to IP cells [49]. Similarly, deletion of Cdon, results in extensive cortical thinning partially due to reduced proliferation and differentiation of cortical progenitors [39].…”