Rhythmic cilia changes support SCN neuron coherence in circadian clock.

The suprachiasmatic nucleus (SCN) drives circadian clock coherence through intercellular coupling, which is resistant to environmental perturbations. We report that primary cilia are required for intercellular coupling among SCN neurons to maintain the robustness of the internal clock in mice. Cilia in neuromedin S-producing (NMS) neurons exhibit pronounced circadian rhythmicity in abundance and length. Genetic ablation of ciliogenesis in NMS neurons enabled a rapid phase shift of the internal clock under jet-lag conditions. The circadian rhythms of individual neurons in cilia-deficient SCN slices lost their coherence after external perturbations. Rhythmic cilia changes drive oscillations of Sonic Hedgehog (Shh) signaling and clock gene expression. Inactivation of Shh signaling in NMS neurons phenocopied the effects of cilia ablation. Thus, cilia-Shh signaling in the SCN aids intercellular coupling.

LUBAC regulates ciliogenesis by promoting CP110 removal from the mother centriole.

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.

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

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.

Clinical relevance of a CD4+ T cell immune function assay in the diagnosis of infection in pediatric living-donor liver transplantation.

The aim of the present study was to investigate the potential of the Immuknow immune cell function assay for the diagnosis of infection after pediatric living-donor liver transplantation (LDLT). Based on clinical data obtained following liver transplantation, 66 patients were divided into infection (n=28) and non-infection (n=38) groups. The following factors were considered in the present analysis: Primary disease, lymphocyte count, tacrolimus plasma concentration/dose (C0/D) ratio, CD4+ T lymphocyte ATP levels, at pre-transplant stage and at weeks 1-4, and 2 and 3 months post-transplant. The CD4+ T lymphocyte ATP values were plotted in a receiver operating characteristic (ROC) curve. The CD4+ T lymphocyte ATP value of the infection group was significantly lower compared with that of the non-infection group (188.6±93.5 vs. 424.4±198.1 ng/ml, respectively; P<0.05). No correlation was observed between the ATP value and tacrolimus plasma C0/D ratio (R2=0.0001484); however, a correlation was reported between the ATP value and lymphocyte count (R2=0.2149). Analysis of the ROC curve indicated that the ATP levels of CD4+ T cells were significantly associated with the diagnostic value of infection (area under the curve=0.866). These findings suggest that low CD4+ T lymphocyte ATP levels may be an independent risk factor for infection following pediatric LDLT, and that the Immuknow assay may be used as a tool to evaluate T lymphocyte function in such patients to predict the risk of infection.