Loss of Suppressor of Fused in Mid-Corticogenesis Leads to the Expansion of Intermediate Progenitors

Abstract

Neural progenitors in the embryonic neocortex must be tightly regulated in order to generate the correct number and projection neuron subtypes necessary for the formation of functional neocortical circuits. In this study, we show that the intracellular protein Suppressor of Fused (Sufu) regulates the proliferation of intermediate progenitor (IP) cells at later stages of corticogenesis to affect the number of Cux1+ upper layer neurons in the postnatal neocortex. This correlates with abnormal levels of the repressor form of Gli3 (Gli3R) and the ectopic expression of Patched 1 (Ptch1), a Sonic Hedgehog (Shh) target gene. These studies reveal that the canonical role of Sufu as an inhibitor of Shh signaling is conserved at later stages of corticogenesis and that Sufu plays a crucial role in regulating neuronal number by controlling the cell cycle dynamics of IP cells in the embryonic neocortex.

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

“…Downstream of Shh receptors, Sufu and Gli have been shown to affect progenitor proliferation. Deletion of Sufu at E13.5 result in ectopic activation of Shh activity leading to an increase in the proliferation of IPs in the SVZ, and consequently, an increase in upper layer 4 PNs [50]. Similarly, reduction or complete removal of Gli3R accelerate the cell cycle [51] and ultimately lead to the failure of RG progenitors to self-renew [32].…”

Suppressor of Fused controls the proliferation of postnatal neural stem and precursor cells via a Gli3-dependent mechanism

“…The lack of any significant changes in OB interneurons prompted us to further examine the fate of NSCs and TACs in the dorsal V-SVZ of hGFAP cre/+ ;Sufu fl/fl mice. We previously observed similar expansion of specific cortical progenitors in the embyronic neocortex of conditional Sufu knockouts and found that many were unable to survive (Yabut et al , 2016). Therefore, we investigated whether cells in the dorsal V-SVZ of the neonatal hGFAP cre/+ ;Sufu fl/fl mice were similarly unstable and became apoptotic.…”

“…Tbr2+ neural progenitors that typically originate from the embryonic cortical progenitors were significantly reduced whereas Gsx2+ neural progenitors that originate from the embryonic ganglionic eminence (Stenman, Toresson and Campbell, 2003; Brill et al , 2009) were significantly increased. We previously reported that loss of Sufu results in the increase in proliferation of cortical progenitors (resulting in an increase in superficial layer projection neurons in the neocortex) and oligodendrogenesis in the E16.5 neocortex of hGFAP-Cre;Sufu-fl mice (Yabut et al , 2016; Winkler et al , 2018). Thus, two possibilities could explain the reduction in Tbr2+ progenitors: 1) cortical progenitors that generate V-SVZ NSCs were re-specified towards the gliogenic lineage, and/or 2) exhaustion of the cortical RG pool has occurred.…”

Unraveling the transcriptional networks that drive oligodendrocyte fate specification in Sonic hedgehog-responsive neocortical progenitors

“…Later in corticogenesis, however, Shh signaling increases in the dorsal forebrain and is required for initiation of oligodendrogenesis. This is accomplished partly by decreased expression of Sufu (Yabut et al, 2015;Yabut et al, 2016), as well as increased Shh ligand brought in by interneurons migrating from the ventral forebrain (Winkler et al, 2018). In this way, tight control over the levels and timing of Shh signals confers both spatial patterning early in development and the later switch from neurogenesis to oligodendrogenesis.…”

“…Interestingly, recent studies together with our data presented here suggest that the molecular mechanisms involved in these dual roles might be very similar. Genetic ablation of the Shh repressor, Sufu, in the early dorsal forebrain leads to overactivation of Shh-mediated transcription, resulting in patterning defects in dorsal progenitors (Yabut et al, 2015;Yabut et al, 2016;Yabut et al, 2020). The mis-specified dorsal progenitors ectopically express ventral identity genes, including Gsx1/2, Dlx1/2, Olig2 and Ascl1, and downregulate dorsal identity genes like Emx1/2 and Pax6 (Yabut et al, 2015;Yabut et al, 2020).…”