Coordination of canonical and noncanonical Hedgehog signalling pathways mediated by WDR11 during primordial germ cell development

Abstract

WDR11, a gene associated with Kallmann syndrome, is important in reproductive system development but molecular understanding of its action remains incomplete. We previously reported that Wdr11-deficient embryos exhibit defective ciliogenesis and developmental defects associated with Hedgehog (HH) signalling. Here we demonstrate that WDR11 is required for primordial germ cell (PGC) development, regulating canonical and noncanonical HH signalling in parallel. Loss of WDR11 disrupts PGC motility and proliferation driven by the cilia-independent, PTCH2/GAS1-dependent noncanonical HH pathway. WDR11 modulates the growth of somatic cells surrounding PGCs by regulating the cilia-dependent, PTCH1/BOC-dependent canonical HH pathway. We reveal that PTCH1/BOC or PTCH2/GAS1 receptor context dictates SMO localisation inside or outside of cilia, respectively, and loss of WDR11 affects the signalling responses of SMO in both situations. We show that GAS1 is induced by PTCH2-specific HH signalling, which is lost in the absence of WDR11. We also provide evidence supporting a role for WDR11 in ciliogenesis through regulation of anterograde intraflagellar transport potentially via its interaction with IFT20. Since WDR11 is a target of noncanonical SMO signalling, WDR11 represents a novel mechanism by which noncanonical and canonical HH signals communicate and cooperate.

The journey of a generation: advances and promises in the study of primordial germ cell migration

“…Indeed, TGFβ may impact PGC migration indirectly by regulating collagen deposition in mouse ( Chuva de Sousa Lopes et al, 2005 ) and Jak/Stat is required for sex-specific gonad development in flies ( Wawersik et al, 2005 ). Manipulation of Hedgehog signaling has a profound impact on PGC migration in Drosophila , zebrafish and mice ( Deshpande et al, 2001 ; Mich et al, 2009 ; Kim et al, 2020 ; Lee et al, 2023 ). However, the key Hedgehog response factor, Smoothened, is not required for zebrafish or fly PGC migration, and Hedgehog is not required for fly PGC attraction in response to known inducing factors ( Mich et al, 2009 ; Renault et al, 2009 ; Kenwrick et al, 2019 ).…”

“…However, the key Hedgehog response factor, Smoothened, is not required for zebrafish or fly PGC migration, and Hedgehog is not required for fly PGC attraction in response to known inducing factors ( Mich et al, 2009 ; Renault et al, 2009 ; Kenwrick et al, 2019 ). One explanation for these contradicting observations is that Hedgehog, like other signaling cascades, is required for specification and patterning of the tissues PGCs encounter and use along their journey ( Lee et al, 1992 ; Ma et al, 2002 ; Chen et al, 2020 ; Lee et al, 2023 ). Fibroblast growth factor (FGF) signaling is required for PGC migration in mice, zebrafish and flies, although in flies FGF signaling remodels the endoderm to allow PGC passage ( Takeuchi et al, 2005 ; Chang et al, 2020 ; Pares and Ricardo, 2016 ; Seifert and Lehmann, 2012 ).…”