TMCO1 is essential for ovarian follicle development by regulating ER Ca(2+) store of granulosa cells

TMCO1 (transmembrane and coiled-coil domains 1) is an endoplasmic reticulum (ER) transmembrane protein that actively prevents Ca(2+) stores from overfilling. To characterize its physiological function(s), we generated Tmco1(−/−) knockout (KO) mice. In addition to the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, Tmco1(−/−) 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 Ca(2+) load-activated Ca(2+) channel, we have detected a supernormal Ca(2+) signaling in Tmco1(−/−) granulosa cells (GCs). Interestingly, although spontaneous Ca(2+) oscillation pattern was altered, ER Ca(2+) 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 Tmco1(−/−) 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 Ca(2+) 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.