Frizzled3 Is Required for Neurogenesis and Target Innervation during Sympathetic Nervous System Development

The sympathetic nervous system has served as an amenable model system to investigate molecular mechanisms underlying developmental processes in the nervous system. While much attention has been focused on neurotrophic factors controlling survival and connectivity of postmitotic sympathetic neurons, relatively little is known about signaling mechanisms regulating development of sympathetic neuroblasts. Here, we report that Frizzled3 (Fz3), a member of the Wnt receptor family, is essential for maintenance of dividing sympathetic neuroblasts. In Fz3(-/-) mice, sympathetic neuroblasts exhibit decreased proliferation and premature cell cycle exit. Fz3(-/-) sympathetic neuroblasts also undergo enhanced apoptosis, which could not be rescued by eliminating the proapoptotic factor, Bax. These deficits result in reduced generation of sympathetic neurons and pronounced decreases in the size of sympathetic chain ganglia. Furthermore, the axons of sympathetic neurons that persist in Fz3(-/-) ganglia are able to extend out of sympathetic ganglia toward distal targets, but fail to fully innervate final peripheral targets. The cell cycle exit, but not target innervation, defects in Fz3(-/-) mice are phenocopied in mice with conditional ablation of beta-catenin, a component of canonical Wnt signaling, in sympathetic precursors. Sympathetic ganglia and innervation of target tissues appeared normal in mice lacking a core planar cell polarity (PCP) component, Vangl2. Together, our results suggest distinct roles for Fz3 during sympathetic neuron development; Fz3 acts at early developmental stages to maintain a pool of dividing sympathetic precursors, likely via activation of beta-catenin, and Fz3 functions at later stages to promote innervation of final peripheral targets by postmitotic sympathetic neurons.