Context-dependent ciliary regulation of hedgehog pathway repression in tissue morphogenesis

by Sun-Hee Hwang, Kevin Andrew White, Bandarigoda Nipunika Somatilaka, Baolin Wang, Saikat Mukhopadhyay

A fundamental problem in tissue morphogenesis is identifying how subcellular signaling regulates mesoscale organization of tissues. The primary cilium is a paradigmatic organelle for compartmentalized subcellular signaling. How signaling emanating from cilia orchestrates tissue organization —especially, the role of cilia-generated effectors in mediating diverse morpho-phenotypic outcomes—is not well understood. In the hedgehog pathway, bifunctional GLI transcription factors generate both GLI-activators (GLI-A) and GLI-repressors (GLI-R). The formation of GLI-A/GLI-R requires cilia. However, how these counterregulatory effectors coordinate cilia-regulated morphogenetic pathways is unclear. Here we determined GLI-A/GLI-R requirements in phenotypes arising from lack of hedgehog pathway repression (derepression) during mouse neural tube and skeletal development. We studied hedgeh og pathway repression by the GPCR GPR161, and the ankyrin repeat protein ANKMY2 that direct cAMP/protein kinase-A signaling by cilia in GLI-R generation. We performed genetic epistasis betweenGpr161 or Ankmy2 mutants, andGli2/Gli3 knockouts,Gli3R knock-in and knockout ofSmoothened, the hedgehog pathway transducer. We also tested the role of cilia-generated signaling using aGpr161 ciliary localization knock-in mutant that is cAMP signaling competent. We found that the cilia-dependent derepression p...

Source: PLoS Genetics - November 9, 2023 Category: Genetics & Stem Cells Authors: Sun-Hee Hwang Source Type: research