Abstract
KIT signaling is a fundamental regulatory pathway that preserves cellular homeostasis and controls cell development and fate across a wide range of organs and cell types. Consistent with this pleiotropic role, mutations in c-KIT/Kit have been associated with a wide range of phenotypes, including sterility, piebaldism, nevus formation, mastocytosis, and multiple malignancies. The contribution of c-KIT/Kit to reproductive function has attracted sustained attention for several decades, underscoring its essential role in fertility and gonadal biology. KIT expression is observed in oocytes - localized to the oocyte membrane and the cytoplasm - as well as in theca cells and interstitial cells, suggesting a multifaceted role in follicular development. Notably, all Kit mutant models develop primary ovarian insufficiency (POI) with variable onset, characterized by endocrine dysfunction, impaired folliculogenesis, and eventual female infertility. These findings collectively establish KIT signaling as a critical regulator of ovarian integrity, as both gain- or loss-of-function mutations in Kit consistently recapitulate POI-associated phenotypes. However, despite substantial progress, the precise molecular mechanisms by which KIT signaling integrates these pathways to preserve primordial follicle survival and prevent POI remain incompletely understood. Here, we summarize current knowledge of KIT expression and the functional consequences of Kit mutations, with particular emphasis on oocytes across ovarian cell populations and in comparison to other organ systems in humans and mice. We further evaluate the physiological and pathological significance of ovarian KIT signaling in female fertility and highlight crucial knowledge gaps that must be addressed to fully elucidate its role in maintaining ovarian function.