State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA.
Nat Commun. 2021 Jan 28;12(1):662. doi: 10.1038/s41467-021-20986-y.
Dynamic assembly and disassembly of primary cilia controls embryonic development and tissue homeostasis. Dysregulation of ciliogenesis causes human developmental diseases termed ciliopathies. Cell-intrinsic regulatory mechanisms of cilia disassembly have been well-studied. The extracellular cues controlling cilia disassembly remain elusive, however. Here, we show that lysophosphatidic acid (LPA), a multifunctional bioactive phospholipid, acts as a physiological extracellular factor to initiate cilia disassembly and promote neurogenesis. Through systematic analysis of serum components, we identify a small molecular-LPA as the major driver of cilia disassembly. Genetic inactivation and pharmacological inhibition of LPA receptor 1 (LPAR1) abrogate cilia disassembly triggered by serum. The LPA-LPAR-G-protein pathway promotes the transcription and phosphorylation of cilia disassembly factors-Aurora A, through activating the transcription coactivators YAP/TAZ and calcium/CaM pathway, respectively. Deletion of Lpar1 in mice causes abnormally elongated cilia and decreased proliferation in neural progenitor cells, thereby resulting in defective neurogenesis. Collectively, our findings establish LPA as a physiological initiator of cilia disassembly and suggest targeting the metabolism of LPA and the LPA pathway as potential therapies for diseases with dysfunctional ciliogenesis.
原发性纤毛动态组装和拆卸控制胚胎发育和组织稳态。纤毛发生的失调会导致人类发育疾病，称为纤毛病。细胞内纤毛拆卸的调节机制已经得到了很好的研究。然而，控制纤毛拆卸的细胞外信号仍然难以捉摸。在这里，我们表明，溶血磷脂酸（LPA），一种多功能生物活性磷脂，作为一种生理细胞外因子，启动纤毛拆卸并促进神经发生。通过对血清成分的系统分析，我们确定小分子 LPA 是触发纤毛拆卸的主要驱动因素。LPA 受体 1（LPAR1）的基因失活和药理学抑制消除了血清触发的纤毛拆卸。LPA-LPAR-G 蛋白途径通过分别激活转录共激活因子 YAP/TAZ 和钙/CaM 途径，促进纤毛拆卸因子-Aurora A 的转录和磷酸化。在小鼠中敲除 Lpar1 会导致神经祖细胞中纤毛异常伸长和增殖减少，从而导致神经发生缺陷。总之，我们的发现确立了 LPA 作为纤毛拆卸的生理启动子，并表明靶向 LPA 的代谢和 LPA 途径可能是治疗纤毛发生功能障碍疾病的潜在疗法。
