Sonic Hedgehog—‘Jack-of-All-Trades’ in Neural Circuit Formation

Abstract

As reflected by the term morphogen, molecules such as Shh and Wnts were identified based on their role in early development when they instruct precursor cells to adopt a specific cell fate. Only much later were they implicated in neural circuit formation. Both in vitro and in vivo studies indicated that morphogens direct axons during their navigation through the developing nervous system. Today, the best understood role of Shh and Wnt in axon guidance is their effect on commissural axons in the spinal cord. Shh was shown to affect commissural axons both directly and indirectly via its effect on Wnt signaling. In fact, throughout neural circuit formation there is cross-talk and collaboration of Shh and Wnt signaling. Thus, although the focus of this review is on the role of Shh in neural circuit formation, a separation from Wnt signaling is not possible.

The Elegance of Sonic Hedgehog: Emerging Novel Functions for a Classic Morphogen

“…In ferrets, Gli1 expression is significantly higher in the ventricular zone (VZ) area that generates a thick subventricular zone (SVZ) containing many oRG, than in the VZ area that gives rise to a thin SVZ containing fewer oRG (de Juan Romero et al, 2015). Consistent with this, in human cerebral organoids (Lancaster et al, 2013), blocking SHH signaling decreases the number of oRG detected in human cerebral organoids (Wang et al, 2016). GLI1 transcription is significantly higher in human fetal neocortex than in mouse embryonic cortex (Wang et al, 2016), consistent with more abundant oRG and IPs in human than mouse fetal cortex.…”

“…In mice, perturbations in Shh signaling cause defective proliferation of IPs and microcephaly (Komada et al, 2008). Furthermore, a recent study showed that Shh signaling is sufficient for both IP and oRG expansion and neocortical growth (Wang et al, 2016). Remarkably, elevated Shh signaling increases upper layer neuron production from mid-corticogenesis at embryonic day 13.5 (E13.5) on, leading to neocortical growth and folding in the otherwise-smooth mouse neocortex.…”

“…Ectopic activation of high Shh signaling, via induction of the SMOM2 allele, which encodes a tumor-derived constitutively active SMO protein, elicits two developmental characteristics that are absent in mouse but have been proposed to be necessary and sufficient for the evolution of an expanded and folded neocortex: oRG expansion and recurrent self-amplifying IP divisions (Lewitus et al, 2014). Elevated Shh signaling in early corticogenesis (E9 -E10) misspecifies cortical NPs, and decreases IPs (Dave et al, 2011;Shikata et al, 2011;Wang et al, 2011;Yabut et al, 2015), demonstrating developmental stage-specific functions of Shh signaling.…”

“…Shh signaling is also important for neocortical growth in gyrencephalic species. GLI1, the expression of which provides a faithful readout of Shh signaling, is highly expressed in human vRG (Wang et al, 2016) and mutations disrupting Shh signaling cause microcephaly in humans (Heussler et al, 2002;Derwiń ska et al, 2009;Izumi et al, 2011). In ferrets, Gli1 expression is significantly higher in the ventricular zone (VZ) area that generates a thick subventricular zone (SVZ) containing many oRG, than in the VZ area that gives rise to a thin SVZ containing fewer oRG (de Juan Romero et al, 2015).…”

Smoothened receptor Signaling regulates the developmental shift of GABA polarity in rat somatosensory cortex

“…In the adult hippocampus, Shh plays an essential role in neurogenesis in the dentate gyrus (Antonelli et al, 2019;Breunig et al, 2008). In addition, Shh receptors Ptch1 and Smo are also expressed at the synaptic junction of the immature and adult hippocampus (Charytoniuk et al, 2002;Mitchell et al, 2012;Petralia et al, 2011), suggesting other roles than control of neurogenesis (Zuñiga and Stoeckli, 2017). For instance, Shh was reported to exert a modulatory action on neuronal electrical activity in the adult brain (Bezard et al, 2003;Pascual et al, 2005) and more recently Shh signaling has been shown to regulates the formation of glutamatergic and GABAergic terminals in hippocampal neurons (Mitchell et al, 2012).…”