Liu Xiaoliang, Yam Patricia T, Schlienger Sabrina, Cai Eva, Zhang Jingyi, Chen Wei-Ju, Torres Gutierrez Oscar, Jimenez Amilburu Vanesa, Ramamurthy Vasanth, Ting Alice Y, Branon Tess C, Cayouette Michel, Gen Risako, Marks Tessa, Kong Jennifer H, Charron Frédéric, Ge Xuecai
Department of Molecular and Cell Biology, University of California, Merced, Merced, CA, 95340, USA.
Montreal Clinical Research Institute (IRCM), Montreal, QC, H2W 1R7, Canada.
Nat Commun. 2024 Apr 25;15(1):3365. doi: 10.1038/s41467-024-47244-1.
Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identify Numb as a ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impedes Sonic hedgehog (Shh)-induced Ptch1 exit from the cilium, resulting in reduced Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into cell fates reliant on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.
刺猬信号通路（Hh）依赖于初级纤毛，这是一种细胞表面细胞器，作为细胞的信号枢纽。利用邻近标记和定量蛋白质组学技术，我们确定Numb是一种纤毛蛋白，可正向调节Hh信号通路。Numb定位于纤毛口袋，并作为一种内吞衔接蛋白，将Ptch1纳入网格蛋白包被的小泡中，从而促进Ptch1从纤毛中排出，这是Hh信号通路激活的关键步骤。Numb缺失会阻碍音猬因子（Shh）诱导的Ptch1从纤毛中排出，导致Hh信号通路减弱。脊髓神经祖细胞中Numb缺失会减少Shh诱导的向依赖高Hh活性的细胞命运的分化。发育中的小脑中Numb的基因敲除会损害颗粒细胞前体的增殖，这是一个依赖Hh的过程，导致小脑尺寸减小。这项研究强调了Numb在Hh信号激活过程中作为纤毛Ptch1水平调节剂的作用，并证明了纤毛口袋介导的内吞作用在细胞信号传导中的关键作用。
