Defects in Follicle Development and Fertility in FST288-Only Mice.

Abstract

The processes of germ cell proliferation and primordial follicle formation are critical for establishing the reproductive potential of mammalian females. Once the proliferating germ cells arrest in meiosis, the resulting germ cell nests break down in a process that involves migration and association of somatic pre-granulosa cells. While the role of steroid hormones in regulating this process has been known for some time, critical roles for other hormones like activin have recently been elucidated. Activin action is regulated in gonads by the soluble antagonist follistatin (FST). We recently created a genetically altered mouse line in which the Fst gene was altered to prevent production of 2 isoforms of FST and allowing only the FST288 isoform to be produced. Unlike the global Fst knockout which dies immediately after birth, the FST288-Only mouse survives to adulthood and displays reproductive and metabolic phenotypes reflecting important roles for FST in adult physiology. Reproductive defects include a surfeit of primordial follicles at birth, more rapid demise of these follicles before puberty, and a reduced primordial follicle pool in adults that leads to a premature ovarian failure (POF) like phenotype. Recent findings indicate that altered activin signaling is at least partially responsible for these defects that involve delayed germ cell nest breakdown and associated apoptosis. These observations expand the list of critical roles for activin and FST in regulating reproductive physiology in mammals. Moreover, the POF phenotype of the FST288-Only mouse may allow identification of mechanisms involved in idiopathic human POF. (platform)