Emerging mechanisms in morphogen‐mediated axon guidance

Abstract

Early in animal development, gradients of secreted morphogenic molecules, such as Sonic hedgehog (Shh), Wnt and TGFbeta/Bmp family members, regulate cell proliferation and determine the fate and phenotype of the target cells by activating well-characterized signalling pathways, which ultimately control gene transcription. Shh, Wnt and TGFbeta/Bmp signalling also play an important and evolutionary conserved role in neural circuit assembly. They regulate neuronal polarization, axon and dendrite development and synaptogenesis, processes that require rapid and local changes in cytoskeletal organization and plasma membrane components. A key question then is whether morphogen signalling at the growth cone uses similar mechanisms and intracellular pathway components to those described for morphogen-mediated cell specification. This review discusses recent advances towards the understanding of this problem, showing how Shh, Wnt and TGFbeta/Bmp have adapted their 'classical' signalling pathways or adopted alternative and novel molecular mechanisms to influence different aspects of neuronal circuit formation.

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

“…Shh signaling appears to regulate not only neural progenitor cell division but also cell fate specification and neuronal maturation (27), suggesting that the APP/AICD-dependent derangement of the Shh pathway in the DS brain may underlie, in addition to proliferation impairment, defective cell fate specification and neuronal maturation. Moreover, increased levels of the sAPP fragment may also contribute to derangement of these processes (20) in the DS brain.…”

Atypical Protein Kinase Cι Is Required for Wnt3a-dependent Neurite Outgrowth and Binds to Phosphorylated Dishevelled 2

“…Wnt signaling stimulates axonal remodeling, pathfinding, dendritic arborization, and neuronal connectivity in the central nervous system (5-7). Many Wnt signaling components have been implicated in neurite outgrowth (7)(8)(9). For instance, Wnt7b induces dendritic morphogenesis in mouse hippocampal neurons via a noncanonical pathway including Dvl, Rac, and JNK (10).…”

Shh goes multidirectional in axon guidance

“…Although interaction among these proteins might be important for efficient Shh reception [13], it is well established that Shh binding to Ptch activates signal transduction in Shhreceiving cells. In basal conditions, Ptch inhibits Smo, but upon ligand binding, this inhibition is released and Smo activates a cascade that leads to control of gene transcription and likely to the activation of local second messengers in growth cones [14]. Song et al [7] observed that Ptch and Smo localized at the surface of serotoninergic caudal raphe axons as they descend along the spinal cord and demonstrated that Ptch and Smo function is required for multidirectional Shh repellent activity.…”

“…Multidirectional guidance by a single signal also raises the perhaps general question of how each individual axon senses the absolute concentration of a given guidance cue and interprets it accordingly. An important contributing factor might be the type and level of surface receptors present in each growth cone [14]. As mentioned above, Shh reception involves different transmembrane proteins that appear to interact with Ptch [13], even though it is unclear whether and how this interaction modifies signal transduction.…”

“…As mentioned above, Shh reception involves different transmembrane proteins that appear to interact with Ptch [13], even though it is unclear whether and how this interaction modifies signal transduction. Expression of Boc, Hip or Gas1, which have also been implicated in axon guidance [14], might participate in Shh-mediated repulsion of caudal raphe neurons, providing a possible alternative explanation for the incomplete penetrance of the raphespinal tract phenotype after alteration of Shh signaling in vivo.…”