Journal
CELL DEATH AND DIFFERENTIATION
Volume 25, Issue 9, Pages 1686-1701Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41418-018-0067-x
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Funding
- National Key Research and Development Program of China [2017YFC1001001, NSFC91754204, 81630078, 31471331, 31670822, 81371415, 31570816]
- CAS Strategic Priority Research Program [XDA16010107, XDB14030300]
- State Key Laboratory of Membrane Biology
- CAS Key Laboratory of Genomic and Precision Medicine
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TMCO1 (transmembrane and coiled-coil domains 1) is an endoplasmic reticulum (ER) transmembrane protein that actively prevents Ca2+ stores from overfilling. To characterize its physiological function(s), we generated Tmco(1-/-) knockout (KO) mice. In addition to the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, Tmco(1-/-) females manifest gradual loss of ovarian follicles, impaired ovarian follicle development, and subfertility with a phenotype analogous to the premature ovarian failure (POF) in women. In line with the role of TMCO1 as a Ca2+ load-activated Ca2+ channel, we have detected a supernormal Ca2+ signaling in Tmco(1-/-) granulosa cells (GCs). Interestingly, although spontaneous Ca2+ oscillation pattern was altered, ER Ca2+ stores of germinal vesicle (GV) stage oocytes and metaphase II (MII) arrested eggs were normal upon Tmco1 ablation. Combined with RNA-sequencing analysis, we also detected increased ER stress-mediated apoptosis and enhanced reactive oxygen species (ROS) level in Tmco(1-/-) GCs, indicating the dysfunctions of GCs upon TMCO1 deficiency. Taken together, these results reveal that TMCO1 is essential for ovarian follicle development and female fertility by maintaining ER Ca2+ homeostasis of GCs, disruption of which causes ER stress-mediated apoptosis and increased cellular ROS level in GCs and thus leads to impaired ovarian follicle development.
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