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bioRxiv · 10.1101/2021.01.07.425654

Gpr161 ciliary pools prevent hedgehog pathway hyperactivation phenotypes specifically from lack of Gli transcriptional repression

Hwang, S.-h.·Somatilaka, B. N.·White, K.·Mukhopadhyay, S.
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Abstract

The role of compartmentalized cAMP signaling in primary cilia is not well understood. The cilia-localized G-protein-coupled receptor--Gpr161 represses hedgehog pathway via cAMP signaling. Here, by generating knock-in mutant mouse at endogenous Gpr161 locus (mut1), we show that ciliary and extraciliary receptor pools repress hedgehog signaling in a tissue-specific manner. Gpr161mut1 was competent in generating cAMP but did not transit through cilia. Compared to knockout, Gpr161mut1 had delayed embryonic lethality, less upregulation of hedgehog targets and partially down-regulated Gli3-repressor. Ventral-most progenitor expansion in neural tube of Gpr161 knockout occurred in a Gli2-activator-dependent manner but was not seen in Gpr161mut1. Intermediate-level ventralization occurred from Gpr161 lack specifically in cilia but was restored by increased extraciliary mutant generating Gli3-repressor. Morphogenesis in limb buds and midface that require Gli-repressor manifested hedgehog hyperactivation phenotypes-- polydactyly and midfacial widening--in Gpr161mut1. Thus, ciliary and extraciliary cAMP signaling establishes tissue-specific Gli-repressor thresholds in dictating morpho-phenotypic outcomes. Impact statementO_ST_ABSSignaling by CiliaC_ST_ABSSignaling by cAMP specifically in cilia directs tissue-specific morphogenesis

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Hwang, S.-h., Somatilaka, B. N., White, K., Mukhopadhyay, S.. 2021-01-07. Gpr161 ciliary pools prevent hedgehog pathway hyperactivation phenotypes specifically from lack of Gli transcriptional repression. https://doi.org/10.1101/2021.01.07.425654

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