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 transduce diverse signals in embryonic development and adult tissues. Defective ciliogenesis results in a series of human disorders collectively known as ciliopathies. The CP110–CEP97 complex removal from the mother centriole is an early critical step for ciliogenesis, but the underlying mechanism for this step remains largely obscure. Here, we reveal that the linear ubiquitin chain assembly complex (LUBAC) plays an essential role in ciliogenesis by targeting the CP110–CEP97 complex. LUBAC specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole in ciliogenesis. We further identify that a pre-mRNA splicing factor, PRPF8, at the distal end of the mother centriole acts as the receptor of the linear ubiquitin chains to facilitate CP110 removal at the initial stage of ciliogenesis. Thus, our study reveals a direct mechanism of regulating CP110 removal in ciliogenesis and implicates the E3 ligase LUBAC as a potential therapy target of cilia-associated diseases, including ciliopathies and cancers.

The internal circadian rhythm is controlled by the central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN). SCN drives coherent and synchronized circadian oscillations via intercellular coupling, which are resistant to environmental perturbations. Here we report that primary cilium is a critical device for intercellular coupling among SCN neurons and acts as a gatekeeper to maintain the internal clock in mice. A subset of SCN neurons, namely neuromedin S-producing (NMS) neurons, exhibit cilia dynamics with a pronounced circadian rhythmicity. Genetic ablation of ciliogenesis in NMS neurons enables a rapid phase shift of the internal clock under experimental jet lag conditions. The circadian rhythms of individual neurons in cilia deficient SCN slices lose their coherence following external perturbations. Rhythmic cilia dynamics drive oscillations of Sonic Hedgehog (Shh) signaling and oscillated expressions of multiple circadian genes in SCN neurons. Genetic and chemical inactivation of Shh signaling in NMS neurons phenocopies the effect of cilia ablation. Our findings establish ciliary signaling as a novel interneuronal coupling mechanism in the SCN and may lead to novel therapy of circadian disruption-linked diseases.