Hedgehog signaling promotes basal progenitor expansion and the growth and folding of the neocortex

Abstract

The unique mental abilities of humans are rooted in the immensely expanded and folded neocortex, which reflects the expansion of neural progenitors, especially basal progenitors including basal radial glia (bRGs, also called outer RGs) and intermediate progenitor cells (IPCs). Here, we show that constitutively active Shh signaling expanded bRGs and IPCs and induced folding in the otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreased the number of bRGs and IPCs and the size of the neocortex. SHH signaling was strongly active in the human fetal neocortex but not in the mouse embryonic neocortex, and blocking SHH signaling in human cerebral organoids decreased the number of bRGs. Mechanistically, Shh signaling increased the initial generation and self-renewal of bRGs as well as increasing IPC proliferation. Thus, robust SHH signaling in the human fetal neocortex may contribute to bRG and IPC expansion and neocortical growth and folding.

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

“…Constitutive activation of Shh signaling achieved by expressing a constitutively active form of Smo (SmoM2; [52]) in cortical progenitors in mid-corticogenesis, results in an increase in the proliferation of Tbr2+ IPs and promotes the expansion of basal RGs (bRGs) [53]. bRGs are neural progenitors that exist in very small numbers in the mouse but are a predominant progenitor population in the developing human neocortex [54, 55].…”

“…In humans and likely other primate species, Dlx2 and Ascl1 are highly expressed in the fetal proliferative zones of the neocortex and may generate a subpopulation of GABAergic interneurons [64–67]. Given the expansion of bRG progenitors in SmoM2-expressing cortical progenitors, human cortical progenitors could have also acquired the ability to generate GABAergic interneurons partially due to increasing Shh signaling activity observed in the fetal human neocortex [53]. Indeed, detectable Shh mRNA is observed in the proliferative outer SVZ (where bRGs are largely localized), RG progenitors, and early post-mitotic neurons in the human fetal neocortex at mid-gestation (at ∼20 gestational weeks), a time of active cortical neurogenesis [53, 68, 69].…”

“…Given the expansion of bRG progenitors in SmoM2-expressing cortical progenitors, human cortical progenitors could have also acquired the ability to generate GABAergic interneurons partially due to increasing Shh signaling activity observed in the fetal human neocortex [53]. Indeed, detectable Shh mRNA is observed in the proliferative outer SVZ (where bRGs are largely localized), RG progenitors, and early post-mitotic neurons in the human fetal neocortex at mid-gestation (at ∼20 gestational weeks), a time of active cortical neurogenesis [53, 68, 69]. Furthermore, cultured human RG cells are Shh-responsive, and in the presence of exogenous Shh, can differentiate into Nkx2.1 lineage GABAergic interneurons [70].…”

Transformation of the Radial Glia Scaffold Demarcates Two Stages of Human Cerebral Cortex Development

“…Recent studies also suggest that local expansion of OSVZ progenitors through increased generation or self-renewal may contribute to early stereotyped folding of the cortical plate (de Juan Romero et al, 2015; Dehay et al, 1996; Dehay et al, 1989; Dehay et al, 2001; Florio et al, 2015; Kriegstein et al, 2006; Nonaka-Kinoshita et al, 2013; Stahl et al, 2013; Wang et al, 2016). In agreement with findings in the ferret cortex (Reillo and Borrell, 2012; Reillo et al, 2011), we observed fewer oRG cells underneath the human calcarine sulcus than the adjacent gyrus during mid-neurogenesis (Figure 4D).…”

Counter-Balance Between Gli3 and miR-7 Is Required for Proper Morphogenesis and Size Control of the Mouse Brain

“…Constitutively active Shh signaling leads to higher proportion of bRGs and IPs, and enlarged brains and midline folding, which is similar to brain defects of Gli3 knockout mice (Rallu et al, 2002; Wang et al, 2016). Reports from us indicate that Gli3 regulates brain size and midline cortical structure, which is potentially through modulating the Shh signaling as either an activator or a suppressor.…”