Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.
Kernel Diagnostic Laboratories LTD, London, UK.
Sci Rep. 2023 Jul 29;13(1):12309. doi: 10.1038/s41598-023-38017-9.
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.
WDR11 是一种与 Kallmann 综合征相关的基因，它在生殖系统发育中很重要，但对其作用的分子理解还不完全。我们之前报道过，Wdr11 缺陷型胚胎表现出纤毛发生缺陷和与 Hedgehog（HH）信号相关的发育缺陷。在这里，我们证明 WDR11 是原始生殖细胞（PGC）发育所必需的，平行调节经典和非经典 HH 信号。WDR11 的缺失破坏了由纤毛非依赖性、PTCH2/GAS1 依赖性非经典 HH 途径驱动的 PGC 运动和增殖。WDR11 通过调节纤毛依赖性、PTCH1/BOC 依赖性经典 HH 途径来调节围绕 PGC 的体细胞的生长。我们揭示了 PTCH1/BOC 或 PTCH2/GAS1 受体的情况分别决定 SMO 在纤毛内或纤毛外的定位，而 WDR11 的缺失会影响 SMO 在这两种情况下的信号反应。我们表明 GAS1 是由 PTCH2 特异性 HH 信号诱导的，而在没有 WDR11 的情况下，这种信号会丢失。我们还提供了支持 WDR11 通过调节正向鞭毛内运输来参与纤毛发生的证据，这可能是通过与 IFT20 的相互作用实现的。由于 WDR11 是非经典 SMO 信号的靶标，因此 WDR11 代表了非经典和经典 HH 信号通信和合作的新机制。
