1. Academic Validation
  2. LPA signaling acts as a cell-extrinsic mechanism to initiate cilia disassembly and promote neurogenesis

LPA signaling acts as a cell-extrinsic mechanism to initiate cilia disassembly and promote neurogenesis

  • Nat Commun. 2021 Jan 28;12(1):662. doi: 10.1038/s41467-021-20986-y.
Huai-Bin Hu  # 1 Zeng-Qing Song  # 1 Guang-Ping Song 1 Sen Li 1 Hai-Qing Tu 1 Min Wu 1 Yu-Cheng Zhang 1 Jin-Feng Yuan 1 Ting-Ting Li 1 Pei-Yao Li 1 Yu-Ling Xu 1 Xiao-Lin Shen 1 Qiu-Ying Han 1 Ai-Ling Li 1 Tao Zhou 1 Jerold Chun 2 Xue-Min Zhang 3 Hui-Yan Li 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
  • 2 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA.
  • 3 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China. zhangxuemin@cashq.ac.cn.
  • 4 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China. hyli@ncba.ac.cn.
  • 5 School of Basic Medical Sciences, Fudan University, Shanghai, China. hyli@ncba.ac.cn.
  • # Contributed equally.
Abstract

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.

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