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

• Published in: Nature communications Vol. 12; no. 1; pp. 662 - 14
• Main Authors: Hu, Huai-Bin, Song, Zeng-Qing, Song, Guang-Ping, Li, Sen, Tu, Hai-Qing, Wu, Min, Zhang, Yu-Cheng, Yuan, Jin-Feng, Li, Ting-Ting, Li, Pei-Yao, Xu, Yu-Ling, Shen, Xiao-Lin, Han, Qiu-Ying, Li, Ai-Ling, Zhou, Tao, Chun, Jerold, Zhang, Xue-Min, Li, Hui-Yan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 13/51; 13/89; 14/19; 14/32; 14/35; 38; 38/109; 38/88; 38/91; 631/80/642; 631/80/86; 64/60; 96; Animals; Calcium; Calcium-binding protein; Calmodulin; Cell Line; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cells (biology); Cilia; Cilia - drug effects; Cilia - genetics; Cilia - metabolism; Developmental disabilities; Dismantling; Embryogenesis; Embryonic growth stage; HEK293 Cells; Heterotrimeric GTP-Binding Proteins - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Inactivation; Lysophosphatidic acid; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurogenesis; Neurogenesis - drug effects; Neurogenesis - genetics; Phospholipids; Phosphorylation; Physiological effects; Physiology; Progenitor cells; Protein Binding; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - metabolism; Regulatory mechanisms (biology); Retinal Pigment Epithelium - cytology; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - metabolism; RNA Interference; Science; Science (multidisciplinary); Signal Transduction; Transcription; Yes-associated protein
• DOI: 10.1038/s41467-021-20986-y
• ISSN: 2041-1723

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. Dynamic assembly and disassembly of primary cilia is critical for tissue development and homeostasis. Here the authors identify lysophosphatidic acid (LPA) as a physiological extracellular factor that initiates cilia disassembly through both YAP/TAZ mediated transcription and calcium/calmodulin mediated activation of Aurora A.