Hedgehog Signaling in Cortical Development

Abstract

The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex.

Keywords: Hedgehog signaling; brain gyrification; cortical development; knockout mouse model; neocortex; neural patterning; neurogenesis; radial glial cells.

Figure 1

Transduction of Hedgehog signaling. In the absence of the ligand, Shh, Ptch1 in the cilium inhibits Smo activity. Sufu sequesters the Gli transcription factors, and the complex translocates through the primary cilium. Gli is phosphorylated by PKA at the basal body and cilia, priming it for proteolytic processing into repressor form. As a result, the transcription of Hh target genes is off (left). Upon Shh binding to Ptch1, the complex exits the cilium. Subsequently, Smo enters the cilium and inactivates PKA. This results in Gli dissociation from the Sufu and its ultimate activation. Active Gli enters the nucleus to initiate the transcription of Hh target genes (right).

Figure 2

The organization and cell types in the developing neocortex (adapted from Toresson et al. 1999). The ventricular zone (VZ) contains the cell body of radial glial cells (RGCs) that attach to the pia surface via the basal process, and to the lateral ventricle surface via the apical process. RGCs may directly generate neurons via asymmetric cell division, and the differentiated neurons migrate to the cortical plate along the RGC’s radial fibers. RGCs also generate multipolar intermediate neural progenitors (INPs) that divide in the subventricular zone (SVZ) to produce neurons. Basal radial glial cells (bRGCs) have a basal process attached to the pial surface, but no apical processes. bRGCs are more abundant in gyrified brains. In rodents, all GABAergic interneurons are generated in the ventral brain, and migrate tangentially to the dorsal cortex; glutamatergic projection neurons are generated in the dorsal brain and migrate radially to the cortical plate. VZ: ventricular zone; SVZ: subventricular zone; IZ: intermediate zone; SP: subplate; CP: cortical plate; MZ: marginal zone. LGE: lateral ganglionic eminence; MGE: medial ganglionic eminence.