LPA signaling acts as a cell-extrinsic mechanism to initiate cilia disassembly and promote neurogenesis.
LPA signaling acts as a cell-extrinsic mechanism to initiate cilia disassembly and promote neurogenesis.
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DOI：
10.1038/s41467-021-20986-y
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发表时间：
2021-01-28
影响因子：
16.6
通讯作者：
Li HY
中科院分区：
文献类型：
--
作者：
Hu HB;Song ZQ;Song GP;Li S;Tu HQ;Wu M;Zhang YC;Yuan JF;Li TT;Li PY;Xu YL;Shen XL;Han QY;Li AL;Zhou T;Chun J;Zhang XM;Li HY
初级纤毛的动态组装和拆解控制着胚胎发育和组织动态平衡。纤毛发生的失调会导致称为纤毛疾病的人类发育疾病。纤毛分解的细胞内在调控机制已经得到了很好的研究。然而，控制纤毛分解的细胞外线索仍然难以捉摸。在这里，我们展示了溶血磷脂酸(LPA)，一种多功能的生物活性磷脂，作为一种生理细胞外因子，启动纤毛分解，促进神经发生。通过对血清成分的系统分析，我们确定了一个小分子-LPA是纤毛分解的主要驱动力。LPA受体1(LPAR1)的遗传失活和药物抑制血清引发的纤毛分解。LPA-LPAR-G蛋白途径通过激活转录共激活因子Yap/TAZ和钙/CaM途径，促进纤毛分解因子Aurora A的转录和磷酸化。在小鼠中，Lpar1的缺失会导致神经前体细胞纤毛异常延长和增殖减少，从而导致神经发生缺陷。总之，我们的发现证实LPA是纤毛分解的生理启动者，并建议将LPA的代谢和LPA途径作为潜在的治疗纤毛发生功能障碍的疾病的靶点。初级纤毛的动态组装和拆卸对组织发育和动态平衡至关重要。在这里，作者确定溶血磷脂酸(LPA)是一种生理细胞外因子，通过YAP/TAZ介导的转录和钙/钙调蛋白介导的Aurora A激活来启动纤毛分解。
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.
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DOI：
10.1093/bioinformatics/bts251
发表时间：
2012-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Jiao X;Sherman BT;Huang da W;Stephens R;Baseler MW;Lane HC;Lempicki RA
通讯作者：
Lempicki RA
影响因子：
64.5
作者：
Kopinke D;Roberson EC;Reiter JF
通讯作者：
Reiter JF
DOI：
10.1083/jcb.135.4.1071
发表时间：
1996-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hecht JH;Weiner JA;Post SR;Chun J
通讯作者：
Chun J
影响因子：
8.8
作者：
Kostic, Milos;Paridaen, Judith T. M. L.;Huttner, Wieland B.
通讯作者：
Huttner, Wieland B.
影响因子：
11.4
作者：
Lee, Kyung Ho;Johmura, Yoshikazu;Lee, Kyung S.
通讯作者：
Lee, Kyung S.