Cranial Nerve Development Requires Co-Ordinated Shh and Canonical Wnt Signaling

Cranial nerves govern sensory and motor information exchange between the brain and tissues of the head and neck. The cranial nerves are derived from two specialized populations of cells, cranial neural crest cells and ectodermal placode cells. Defects in either cell type can result in cranial nerve developmental defects. Although several signaling pathways are known to regulate cranial nerve formation our understanding of how intercellular signaling between neural crest cells and placode cells is coordinated during cranial ganglia morphogenesis is poorly understood. Sonic Hedgehog (Shh) signaling is one key pathway that regulates multiple aspects of craniofacial development, but whether it co-ordinates cranial neural crest cell and placodal cell interactions during cranial ganglia formation remains unclear. In this study we examined a new Patched1 (Ptch1) loss-of-function mouse mutant and characterized the role of Ptch1 in regulating Shh signaling during cranial ganglia development. Ptch1Wig/ Wig mutants exhibit elevated Shh signaling in concert with disorganization of the trigeminal and facial nerves. Importantly, we discovered that enhanced Shh signaling suppressed canonical Wnt signaling in the cranial nerve region. This critically affected the survival and migration of cranial neural crest cells and the development of placodal cells as well as the integration between neural crest and placodes. Collectively, our findings highlight a novel and critical role for Shh signaling in cranial nerve development via the cross regulation of canonical Wnt signaling.

颅神经（cranial nerves）负责介导大脑与头颈部组织之间的感觉与运动信息交换。颅神经起源于两类特化细胞群：颅神经嵴细胞（cranial neural crest cells）与外胚层基板细胞（ectodermal placode cells）。任一细胞类群出现缺陷，均可引发颅神经发育异常。尽管目前已明确多种信号通路可调控颅神经形成，但学界对于颅神经节形态发生过程中，神经嵴细胞与基板细胞间的细胞间信号传导如何协同调控，仍知之甚少。音猬因子（Sonic Hedgehog, Shh）信号通路是调控颅面部发育多个环节的关键通路之一，但其是否在颅神经节形成过程中协同调控颅神经嵴细胞与基板细胞的相互作用，目前仍不明确。本研究针对一种新型Patched1（Ptch1）功能缺失型小鼠突变体展开探究，阐明了Ptch1在颅神经节发育过程中调控Shh信号通路的作用机制。Ptch1^Wig/Wig突变体表现出Shh信号通路活性上调，并伴随三叉神经与面神经结构紊乱。值得注意的是，本研究发现增强的Shh信号会抑制颅神经区域内的经典Wnt信号通路，这对颅神经嵴细胞的存活与迁移、基板细胞的发育，以及神经嵴与基板间的整合过程均产生了关键性影响。综上，本研究结果揭示了Shh信号通路通过交叉调控经典Wnt信号通路，在颅神经发育中发挥的全新且关键的作用。