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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cilia / drug effects*
  • Cilia / genetics
  • Cilia / metabolism
  • HEK293 Cells
  • Heterotrimeric GTP-Binding Proteins / metabolism
  • Humans
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neurogenesis / drug effects*
  • Neurogenesis / genetics
  • Protein Binding
  • RNA Interference
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / metabolism
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / drug effects*
  • Retinal Pigment Epithelium / metabolism
  • Signal Transduction*

Substances

  • Lysophospholipids
  • Receptors, Lysophosphatidic Acid
  • Heterotrimeric GTP-Binding Proteins
  • lysophosphatidic acid