Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: TMCO1 is essential for ovarian follicle development by regulating ER Ca²⁺store of granulosa cells. Sun Z et al. (2018) 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 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 Ca²⁺load-activated Ca²⁺channel, we have detected a supernormal Ca²⁺signaling in Tmco1^-/-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 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 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.//////////////////