Abstract
Sonic hedgehog (Shh) signaling occurs concurrently with the many processes that constitute nervous system development. Although Shh is mostly known for its proliferative and morphogenic action through its effects on neural stem cells and progenitors, it also contributes to neuronal differentiation, axonal pathfinding and synapse formation and function. To participate in these diverse events, Shh signaling manifests differently depending on the maturational state of the responsive cell, on the other signaling pathways regulating neural cell function and the environmental cues that surround target cells. Shh signaling is particularly dynamic in the nervous system, ranging from canonical transcription-dependent, to non-canonical and localized to axonal growth cones. Here, we review the variety of Shh functions in the developing nervous system and their consequences for neurodevelopmental diseases and neural regeneration, with particular emphasis on the signaling mechanisms underlying Shh action.
Highlights
The highly complex nature of the central nervous system is due to the copious number of cells it is composed of, and to the number and diversity of connections between these cells
While this interaction is necessary for the proliferation of neural stem cells, it is not required for neural tube ventral patterning [21], providing an example of the versatility of Sonic hedgehog (Shh) action depending on interactions with additional signaling molecules
Xenopus laevis embryos is accompanied by a switch in Shh signaling from glioma-associated oncogene (Gli) to Ca spike activity dependent, which results in the recruitment of protein kinase A (PKA) and the shutting off of Gli transcriptional activity in the differentiating neuron. (b) Shh action changes when commissural spinal axons cross ventrally the midline from chemoattractant to chemorepellent due to differential, growth cone-localized signaling in mouse embryos
Summary
The highly complex nature of the central nervous system is due to the copious number of cells it is composed of, and to the number and diversity of connections between these cells. Different developmental stages are characterized by sets of specific cellular events, and the temporal and spatial boundaries of the developmental processes that create the nervous system are critically important These boundaries are established by tight regulation of neural cell proliferation, neural progenitor specification, neuronal differentiation, synapse formation and neural plasticity. One potentially simple mechanism of switching from one cellular process to the would be to switch factors by upregulating the expression of a “new” one while downregulating the expression of the “old” one This paradigm does not always seem to apply; Sonic hedgehog (Shh) is a prominent example of a protein that is expressed in both the incipient nervous system and in the adult brain, but whose role varies widely throughout development. We propose a model of Shh signal switching throughout development to accommodate the wide variety of tasks and adapt to the dynamic changes in neural cell function as the nervous system develops and matures
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