Sonic Hedgehog Signaling Confers Ventral Telencephalic Progenitors with Distinct Cortical Interneuron Fates

Abstract

Summary Interneurons in the cerebral cortex regulate cortical functions through the actions of distinct subgroups that express parvalbumin, somatostatin or calretinin. The genesis of the first two subgroups requires the expression of NKX2.1, which is maintained by SHH signaling during neurogenesis. In this paper, we report that mosaic elimination in the medial ganglionic eminence (MGE) of Smo, a key effector of SHH signaling, reveals that MGE progenitors retain a remarkable degree of plasticity during the neurogenic period. SHH signaling prevents the upregulation of GSX2 and conversion of some MGE progenitors to a caudal ganglionic eminence-like fate, and GSX2 functions to promote that fate. In addition, a higher level of SHH signaling promotes the generation of the somatostatin-expressing interneuron at the expense of parvalbumin-expressing subgroup. These results indicate that cortical interneuron diversity, a major determinant of cortical function, is critically influenced by differential levels of SHH signaling within the ventral telencephalon.

Duration of culture and sonic hedgehog signaling differentially specify PV versus SST cortical interneuron fates from embryonic stem cells

“…4G). As our previous studies have demonstrated that the higher levels of Shh signaling induce Nkx6.2 in the dorsal MGE relative to ventral MGE (Xu et al, 2005(Xu et al, , 2010a, and, as the relative levels of Nkx2.1 and Nkx6.2 transcript are similar in high versus low Shh-exposed cultures as they are in dorsal versus ventral MGE cells (Fig. 4I,J), Nkx2.1::mCherry + cells in our high and low Shh protocols have features of dorsal versus ventral MGE, respectively.…”

“…First, whereas, within a given cortical layer, PVand SST-expressing interneurons have similar birthdates (Cavanagh and Parnavelas, 1988;Rymar and Sadikot, 2007), the predominance of PV over SST subgroups in the later-born, superficial cortical layers corresponds to a larger percentage of all SST interneurons being generated earlier than all PV interneurons (Butt et al, 2005;Xu et al, 2010b). Second, higher levels of signaling for the morphogen Shh in dorsal MGE appears to bias those Nkx2.1-expressing progenitors to generate SST-expressing interneurons (Xu et al, 2005(Xu et al, , 2010aWonders et al, 2008) (schematized in Fig. 4A).…”

“…These MGE-derived interneurons require the expression of the transcription factor Nkx2.1 during the progenitor stage (Sussel et al, 1999;Xu et al, 2004;Butt et al, 2008), then downregulate this gene to facilitate migration into the cortex (Nóbrega-Pereira et al, 2008). Upstream of Nkx2.1, sonic hedgehog (Shh) is required for the induction and maintenance of Nkx2.1 (Xu et al, 2005), and higher levels of Shh bias MGE progenitors to SST-expressing interneuron fates, whereas lower levels bias for the PV-expressing subgroup [ (Xu et al, 2010a); but see also (Flandin et al, 2011)]. Downstream of Nkx2.1, its direct target Lhx6 is maintained in MGE-derived interneurons from cell cycle exit through postnatal development and is necessary for their normal development (Lavdas et al, 1999;Sussel et al, 1999;Liodis et al, 2007;Du et al, 2008;Zhao et al, 2008;Flandin et al, 2011;Vogt et al, 2014).…”

Activin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors

“…Shh signalling is required for specifying MGE identity and for the formation of somatostatin and parvalbulim interneurons, and loss of Shh signalling leads to increased calretinin interneuron development in vivo 43 . However, although the CGE develops independently of Shh 44 , during ESC differentiation the inhibition of Shh generates glutamatergic neurons and never gives rise to Gsx2 progenitors or calretinin interneurons 14,28 .…”

GSH2 promoter methylation in pancreatic cancer analyzed by quantitative methylation-specific polymerase chain reaction

“…Conversely, inhibition of Shh signaling suppresses the self-renewal capacity of pancreatic cancer stem cells and reverses chemotherapy resistance (16). Shh may also downregulate GSH2 in ventral telencephalic progenitors (17), suggesting that Shh signaling is able to suppress GSH2 under certain conditions.…”