山口大学大学院医学系研究科分子細胞生理学講座Department of Molecular and Cellular Physiology,Graduate School of Medicine, Yamaguchi University― 136 ―Cilia are microtubular projecting structures that develop on the human cell surface and are mainly classified into autonomous motile "motile cilia" and non-motor "primary cilia" in which diverse channels and receptors accumulate. In nodes in the mammalian embryos, counterclockwise water flow produced by motile cilia in pit cells induces left-right asymmetry in gene expression. In this case, a mechanoreceptive Ca2+ channel, Polycystin-2, localized in primary cilia that develop in crown cells at the left lateral margin of the node senses the nodal flow, and Ca2+ influx from the cilia regulates gene expression. Therefore, the conversion of mechanical information into chemical information by primary cilia is necessary for asymmetry in organ positioning.For primary cilia to sense the extracellular and mechanical force, the cell membrane covering primary cilia (ciliary membrane) is clearly differentiated from other cell membrane regions not only in protein composition but also in lipid composition. In particular, the ciliary membrane is highly enriched in cholesterol, forming a large plasma membrane domain. Prescription of cholesterol synthesis inhibitors statins to pregnant women is contraindicated because of congenital malformations, such as visceral retroversion, in experimental animals treated with statins. However, the mechanism by which low cholesterol levels cause situs inversus is unknown.Cryo-EM analysis has shown that Polycystin-2, a mechanoreceptive calcium ion channel localized in primary cilia, directly binds cholesterol. In this study, we generated mice carrying a missense mutation (PKD2 c.1550T>G, p.L517R) in the cholesterol-binding site of Polycystin-2, which has been detected in a database of autosomal dominant polycystic kidney patients. This homozygous mouse was embryonic lethal and developed multiple cystic kidneys in addition to situs inversus. The mutant protein not only had reduced ion channel activity, but also decreased localization to the ciliary membrane. These results suggest that cholesterol plays a role in left-right determination of organ positioning through the localization of Polycystin-2 to the ciliary Abstractコレステロールによる臓器配置の左右決定機構Cholesterol-mediated determination of left-right asymmetry of organs宮本 達雄Tatsuo Miyamoto
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