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

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.

Primary Cilia and Centrosomes in Neocortex Development

“…The MT-dependent resorption is regulated by AuroraA kinase: It phosphorylates histone deacetylase HDAF6 and thereby triggers tubulin de-acetylation in the axoneme ( Pugacheva et al, 2007 ). Lysophosphatic acid (LPA), a phospholipid derivative, is involved in AuroraA-dependent primary cilium disassembly by activating the YAP/TAZ signaling pathway ( Hu et al, 2021 ). In addition, phosphorylation of AuroraA is catalyzed by a calmodulin/calcium-dependent protein kinase.…”

“…In addition, phosphorylation of AuroraA is catalyzed by a calmodulin/calcium-dependent protein kinase. As a consequence, knockout embryos for the LPA receptor1 (LPAR1) show abnormally long primary cilia and reduced levels of both BPs and neurons ( Hu et al, 2021 ; Figure 2B ). A similar phenotype has been observed for mouse embryos mutant for either CenpJ/CPAP/Sas4, a MT-binding protein involved in centrosome maintenance and spindle orientation, or Kif2a, a kinesin motor protein ( Figure 2B ).…”

Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases

“…Therefore, we suppose that the LPA/LPAR1-YAP axis may have a prospective impact on osteoimmune-mediated osseointegration, but its specific regulatory mechanism needs further clarification. Interestingly, the latest article revealed that LPA/LPAR1 pathway initiated cilia disassembly and promoted neurogenesis by activating the transcriptional coactivators YAP/transcriptional coactivator with a PDZ-binding motif (TAZ) signaling (Hu et al, 2021), which suggests the hypothesis that the role of the LPA/LPAR1-YAP pathway in neurogenesis could be generalized to dental implantation field by establishing osseoperception in bone-implant interface in order to compensate for the missing sensory functions of periodontal ligament. Therefore, osseoperception and osteoimmunology might share the same promising signaling target and synergistically promote bone healing and favorable osseointegration, which may be achieved by interdisciplinary work such as producing a pro-neurogenesis surface, which is also friendly to osteoimmunology by surface modification of implants.…”

Ciliary GPCR‐based transcriptome as a key regulator of cilia length control

“…Therefore, studies on cilia length regulation might reveal essential determinants of energy homeostasis linked to obesity in individuals with ciliopathies, as well as other neuronal functions at the cellular level (23,24). Physiological modulation of ciliary length is achieved through multiple soluble factors, including leptin, lysophosphatidic acid, prostaglandin and lithium (25)(26)(27)(28)(29). However, there is no unified cilia length-determining pathway, as multiple signaling components that alter cilia length regardless of cell cycle period have been identified.…”