Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region

Abstract

The midbrain and anterior hindbrain offer an ideal system in which to study the coordination of tissue growth and patterning in three dimensions. Two organizers that control anteroposterior (AP) and dorsoventral (DV) development are known, and the regulation of AP patterning by Fgf8 has been studied in detail. Much less is known about the mechanisms that control mid/hindbrain development along the DV axis. Using a conditional mutagenesis approach, we have determined how the ventrally expressed morphogen sonic hedgehog (Shh) directs mid/hindbrain development over time and space through positive regulation of the Gli activators (GliA) and inhibition of the Gli3 repressor (Gli3R). We have discovered that Gli2A-mediated Shh signaling sequentially induces ventral neurons along the medial to lateral axis, and only before midgestation. Unlike in the spinal cord, Shh signaling plays a major role in patterning of dorsal structures (tectum and cerebellum). This function of Shh signaling involves inhibition of Gli3R and continues after midgestation. Gli3R levels also regulate overall growth of the mid/hindbrain region, and this largely involves the suppression of cell death. Furthermore, inhibition of Gli3R by Shh signaling is required to sustain expression of the AP organizer gene Fgf8. Thus, the precise spatial and temporal regulation of Gli2A and Gli3R by Shh is instrumental in coordinating mid/hindbrain development in three dimensions.

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

“…Interestingly, Shh is required during development for the specification of several neuronal populations, including DA SNpc. Shh is embryonically secreted from the ventral floor and basal plates, and the absence of Shh leads to a reduction in the number of DA SNpc (Blaess, Corrales, & Joyner, 2006). The described expression of Shh in DA SNpc (Gonzalez‐Reyes et al, 2012) combined with our results suggest a plausible role for Shh in the specification of striatal interneurons.…”

Advances in behavioral genetics: mouse models of autism

“…278 Among multiple other roles, SHH is important for normal embryonic patterning, including the development of midbrain and hindbrain structures. 279,280 One study has suggested that the administration of SHH can partially attenuate the neurotoxic effects of valproic acid on early serotonergic neuronal development. 252 SHH may produce effects through the PI3K pathway, 281 which is also important for normal brain development.…”

Gene expression analysis of the hedgehog signaling cascade in the chick midbrain and spinal cord

“…Recent advances in stem cell technology and breakthroughs in identifying the transcriptional cascades involved in specifying midbrain dopaminergic neurons have renewed interest in understanding how overall midbrain patterning is accomplished (Bayly et al, 2007;Agarwala et al, 2001;Simeone, 2005;Blaess et al, 2006). Two major signaling centers, the midbrain-hindbrain boundary (MHB), and the floor plate have been implicated in establishing midbrain pattern (Marti et al, 1995;Joyner, 1996;Blaess et al, 2006).…”

“…Recent advances in stem cell technology and breakthroughs in identifying the transcriptional cascades involved in specifying midbrain dopaminergic neurons have renewed interest in understanding how overall midbrain patterning is accomplished (Bayly et al, 2007;Agarwala et al, 2001;Simeone, 2005;Blaess et al, 2006). Two major signaling centers, the midbrain-hindbrain boundary (MHB), and the floor plate have been implicated in establishing midbrain pattern (Marti et al, 1995;Joyner, 1996;Blaess et al, 2006). The midbrain/rostral floor plate (rFP) is a source of the signaling molecule Sonic Hedgehog (SHH), whose role in specifying ventral neural cell-fates is well established (Chiang et al, 1996;Jessell, 2000;Agarwala et al, 2001;Fedtsova and Turner, 2001;Blaess et al, 2006).…”

“…Two major signaling centers, the midbrain-hindbrain boundary (MHB), and the floor plate have been implicated in establishing midbrain pattern (Marti et al, 1995;Joyner, 1996;Blaess et al, 2006). The midbrain/rostral floor plate (rFP) is a source of the signaling molecule Sonic Hedgehog (SHH), whose role in specifying ventral neural cell-fates is well established (Chiang et al, 1996;Jessell, 2000;Agarwala et al, 2001;Fedtsova and Turner, 2001;Blaess et al, 2006).…”