Establishing Hedgehog Gradients during Neural Development

Abstract

A morphogen is a signaling molecule that induces specific cellular responses depending on its local concentration. The concept of morphogenic gradients has been a central paradigm of developmental biology for decades. Sonic Hedgehog (Shh) is one of the most important morphogens that displays pleiotropic functions during embryonic development, ranging from neuronal patterning to axon guidance. It is commonly accepted that Shh is distributed in a gradient in several tissues from different origins during development; however, how these gradients are formed and maintained at the cellular and molecular levels is still the center of a great deal of research. In this review, we first explored all of the different sources of Shh during the development of the nervous system. Then, we detailed how these sources can distribute Shh in the surrounding tissues via a variety of mechanisms. Finally, we addressed how disrupting Shh distribution and gradients can induce severe neurodevelopmental disorders and cancers. Although the concept of gradient has been central in the field of neurodevelopment since the fifties, we also describe how contemporary leading-edge techniques, such as organoids, can revisit this classical model.

Distinct patterning responses of wing and leg neuromuscular systems to different preaxial polydactylies

“…Contrary to that, the presence of extra muscles in RA-induced polydactylies is mirrored by the presence and innervation of extra motor nerve projections ( Luxey et al, 2020 ). Given Sonic Hedgehog ’s role as an axon guidance cue in the central nervous system ( Zuñiga and Stoeckli, 2017 ; Douceau et al, 2023 ), future studies should also explore the possibility of such ectopic sources of SHH directly affecting these nerve route choices in the limb mesenchyme. All of these observations so far only consider alterations in innervation patterns in the limb periphery.…”

“…SHH released from the notochord and floor plate is of central importance for early neuron specification in the spinal cord ( Sagner and Briscoe, 2019 ). However, despite its importance as a guidance cue in other developmental contexts ( Zuñiga and Stoeckli, 2017 ; Douceau et al, 2023 ), axonal projection patterns in the limb periphery are thought to be only indirectly affected by SHH. Namely, SHH from the limb Zone of Polarizing Activity (ZPA) modulates the composition and distribution of lateral plate mesoderm-derived axon guidance factors in the limb mesenchyme ( Bonanomi and Pfaff, 2010 ; Bonanomi, 2019 ; Zang et al, 2021 ).…”

SRY-box Transcription Factor 6 Is Expressed Not Only in the Dorsal but Also in the Ventral Zone of the Neural Tube and Is Highly Expressed in the Notochord and Chordoma

“…Sonic hedgehog (SHH) is secreted from the notochord and the floor plate of the neural tube and induces neurons in the ventral neural tube. SHH acts as a morphogen, such that high concentrations induce ventral neurons and the lowest concentrations induce dorsal neurons [ 2 ]. Interestingly, OLIG2-expressing cells as well as NKX2.2-expressing cells were lacking in the SHH secretion area but were located adjacent to the SHH secretion area.…”

ERK signaling expands mammalian cortical radial glial cells and extends the neurogenic period

“…In general, SHH signaling (SHH concentration) exhibits in a ventral high -dorsal low and caudal high -rostral low gradient, whereas FGF-ERK signaling exhibits in a rostral highcaudal low gradient during telencephalon patterning and development 30,69,70 . SHH and FGF8 have a reciprocal regulatory relationship during telencephalon patterning.…”