Divergent roles of Ror2 and noncanonical Wnt signaling in primordial germ cells and their somatic microenvironment

A central question in embryonic development is the extent to which cellular decisions are internally controlled or mediated by the surrounding environment. Primordial germ cells (PGCs) in the mouse embryo are a unique model to address this question because they traverse numerous cell and tissue types during their multi-day migration from the primitive gut to the developing gonads. Despite the conservation of PGC migration across species, mechanisms governing the motility, maturation, survival, and proliferation of these cells in mammals remain largely unknown. In this work, I use genetic mutants, single cell quantitative imaging, and ex vivo cell culture to examine the intrinsic and extrinsic role of noncanonical Wnt signaling in regulating migratory PGC development.Analysis of in vivo PGCs revealed a role for the somatic cell microenvironment in regulating germ cell proliferation. I observed a steady rise in the number of cycling PGCs along the migratory route which correlated with their canonical Wnt activity. In the earliest somatic niche, the hindgut, I show that the noncanonical ligand Wnt5a, and its receptor Ror2, work to antagonize the canonical Wnt pathway and suppress the PGC proliferation. Additionally, Wnt5a primes PGCs to adopt a migratory morphology without providing directional cues. Conditional loss of Ror2 specifically in PGCs phenocopies the temporary burst in proliferation in the hindgut as well as the reported migration defects at the time of gonadal colonization. However, I find a sustained increase in total germ cell number, suggesting that mutant PGCs have improved survival in wild-type soma. Parallel experiments in Xenopus laevis corroborate our findings that Ror2 has divergent functions in PGCs compared to their surrounding microenvironment. These results suggest that PGCs integrate intrinsic and extrinsic Wnt5a-Ror2 signaling to successfully move, expand, and survive on their way to the gonads. The balance of motility and proliferation by the microenvironment via the noncanonical Wnt pathway may function similarly in other migratory cell lineages, such as hematopoietic stem cells and neural crest cells. Further exploration of these cells and their microenvironments will enhance our understanding of the interplay between migration of precursor populations and other simultaneous cell processes critical to their development