Sonic hedgehog regulates the pathfinding of descending serotonergic axons in hindbrain in collaboration with Wnt5a and secreted frizzled‐related protein 1

Abstract

Previous studies have demonstrated that both Wnt5a and Sonic hedgehog (Shh) are involved in regulating the pathfinding of descending serotonergic (5-HT, 5-hydroxytryptamine) axons in an opposite manner in the brainstem. Shh and Wnt signaling pathways interact to guide post-crossing commissural axons, where Shh acts as a repellent directly and shaping the Wnt gradient indirectly by regulating the gradient expression of the frizzled-related protein 1 (Sfrp1). Whether such a mechanism functions in descending 5-HT axon guidance remains unknown. Here, we found that the core components of the Shh and Wnt planar cell polarity signaling pathways are expressed in caudal 5-HT neurons, and the expression gradients of Shh, Sfrp1, and Wnt5a exist simultaneously in hindbrain. Dunn chamber assays revealed that Sfrp1 suppressed the attractive Wnt gradient. Moreover, we found that Shh overexpression led to pathfinding defects in 5-HT axon descending, and the axonal pathfinding defects could be partially rescued by administration of an Sfrp1 antagonist in vivo. Biochemical evidence showed Shh overexpression upregulated the expression of the Sfrp1 gene and interrupted Wnt5a binding to Frizzled-3. Taken together, our results indicate that Shh, Sfrp1, and Wnt5a collaborate to direct the pathfinding of descending 5-HT axons in the brainstem.

Effects of Wnt5a overexpression in spinal cord injury

“…35 Interestingly, this differs from what was observed during CNS development, when both descending and ascending serotonergic axons are attracted by Wnt5a via Fz3. 33,34 Given that the effects of Wnt5a in axonal growth are largely dictated by the available receptors in the axonal membrane, 53 axonal level, but also in neuronal somas, reactive astrocytes and microglia/macrophages, NG2+ glial precursors and oligodendrocytes. 3,4,7 These observations indicate that these cell types are able to respond to Wnt5a and, thus, that this Wnt ligand might be influencing their critical responses to SCI.…”

“…As previously introduced, we aimed to assess whether Wnt5a is able to modulate the regeneration of non-CST axons after SCI. Since the serotonergic system plays a major role in the recovery of motor function, is particularly affected after SCI and is developmentally regulated by this Wnt ligand, [33][34][35] we focused in the evaluation of the descending serotonergic innervation of the ventral horn motor region caudally to the injury site at 126 dpi. As shown (Figure 1A-G), Wnt5a overexpression led to an evident reduction in the presence of 5-HT + innervation in this region at the different evaluated caudal spinal cord levels.…”

“…11,[21][22][23][24][25][26][27][28][29][30][31][32] Based on the previously detailed observations and to further elucidate the potential functions exerted by Wnt5a in the lesioned spinal cord, we aimed to evaluate the effects induced by lentiviral-mediated Wnt5a overexpression in myelin preservation, neuronal and oligodendroglial cell survival, microglial and astroglial reactivity and NG2+ cell response in a clinically relevant model of rat SCI. In addition, we also sought to determine whether the previously detailed involvement of Wnt5a in SCI-related CST regeneration/retraction might be reflected in other axonal tracts, by determining the effects induced by Wnt5a overexpression in the descending serotonergic innervation, which is also influenced by this Wnt ligand during development 33,34 and is particularly affected in this neuropathological condition. 35 Finally, the potential induction of changes in functional recovery elicited by Wnt5a overexpression after SCI was also conveniently assessed.…”

Specific temperament in patients with nevoid basal cell carcinoma syndrome

“…Shh and fibroblast growth factor 8 control the induction in the rostral cluster of serotonergic neurons and are involved in the transcription regulation of serotonergic neuron development in the caudal cluster 6 . Shh also regulates the pathfinding of descending serotonergic axons in the hindbrain in collaboration with Wnt5a and secreted frizzled‐related protein 1 22 …”

Wnt5b-induced PCP/JNK Activation Promotes PD-L1 Expression and the Malignant Phenotype of Non-small Cell Lung Cancer 

“…and Fzd6 control the polarity of developing skin via Wnt/PCP pathway [30]. The binding of Wnt5a to Fzd3 activates noncanonical Wnt signaling [46,47]. Wnt5a and Activated T-lymphocytes triggers tumor cell death, but tumor cells could avoid this immune process so as to proliferate, depending on the immune checkpoint pathway.…”