Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration

Yeonjoo Kim,Martyn T Cobourne,Soo-Hyun Kim,Jiyoung Lee,Maisa Seppala

doi:10.1038/s41467-020-15897-3

Abstract

Gas1 and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear. Here we demonstrate, using primordial germ cell migration in mouse as a developmental model, that specific hetero-complexes of Ptch2/Gas1 and Ptch1/Boc mediate the process of Smo de-repression with different kinetics, through distinct modes of Hedgehog ligand reception. Moreover, Ptch2-mediated Hedgehog signalling induces the phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a previously unknown Ptch2-specific signal pathway. We propose that although Ptch1 and Ptch2 functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas1 may determine the outcome of Hedgehog signalling through compartmentalisation and modulation of Smo-downstream signalling. Our study identifies the existence of a divergent Hedgehog signal pathway mediated by Ptch2 and provides a mechanism for differential interpretation of Hedgehog signalling in the germ cell niche.

Highlights

Gas[1] and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear
To evaluate the involvement of Hh signalling during the migration of post-specification Primordial germ cells (PGCs) in mouse, we examined the spatiotemporal expression of Hh pathway genes in the gonadal anlage of E9.5–11.5 embryos
We found that Ptch[1], Gli1/2/3, Dhh and Shh, but not Ihh, were expressed along with a germ cell marker Stella in the HG at E9.5 and in the genital ridges (GR) at E10.5–11.5, where PGCs localise (Fig. 1a)

Summary

Introduction

Gas[1] and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear. We demonstrate, using primordial germ cell migration in mouse as a developmental model, that specific hetero-complexes of Ptch2/Gas[1] and Ptch1/Boc mediate the process of Smo derepression with different kinetics, through distinct modes of Hedgehog ligand reception. We propose that Ptch[1] and Ptch[2] functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas[1] may determine the outcome of Hedgehog signalling through compartmentalisation and modulation of Smo-downstream signalling. Our study identifies the existence of a divergent Hedgehog signal pathway mediated by Ptch[2] and provides a mechanism for differential interpretation of Hedgehog signalling in the germ cell niche. Cells lacking Ptch[1] remain sensitive to Hh in a chemotaxis assay, and Ptch[2] can mediate Hh-induced motile responses in the absence of Ptch[124]

Methods

Results

Conclusion