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(MS9) REGULATION OF GONADAL ACTIVIN/BMPs. Schneyer, Alan1, Xia, Yin1, Mukherjee, Abir1, Sidis, Yisrael1, 1 Massachusetts General Hospital, Boston, MA ABSTRACT- Activins and BMPs are members of the TGF KEY WORDS: follistatin, TGF |
superfamily of growth and differentiation factors. Activins have a variety of local autocrine/paracrine activities within the gonad, including modulation of granulosa cell proliferation and differentiation in females and regulation of Sertoli cell proliferation and function in males. Additional knockout and cell culture studies indicate that BMPs also have important roles in germ cell development and gonadal function. Importantly, both activins and BMPs are regulated by extracellular proteins that bind these ligands and neutralize their actions. The main activin inhibitors include follistatin (FST), follistatin like-3 (FSTL3), and inhibin while BMPs are regulated primarily by noggin and chordin. Inhibin acts largely as an endocrine regulator of pituitary activin while FST is made in many of the same tissues as activin and acts more in the autocrine/paracrine mode. The importance of FST in regulating activin and possibly BMPs was demonstrated by the FST knockout in which homozygotes die from multiple defects a few hours after birth, while transgenic overexpression of FST causes disruption of ovarian and testicular architecture and function. Similarly, the significance of regulating BMPs is emphasized by the perinatal lethality of the noggin knockout. Like FST, FSTL3 binds and inhibits activins, and to a lesser extent, myostatin. Unlike FST, FSTL3 is also found in the nucleus, and is expressed at high levels in placenta and testis. Gonadal overexpression of FSTL3 resulted in reduced testis weight, sperm production and fertility in males along with Leydig cell hyperplasia. In addition, a number of tubules were observed that were devoid of germ cells. Females also had lower fertility with an increase in atretic follicles along with a reduced number of antral follicles. This phenotype is similar to, but not as severe as that of FST transgenic mice. Surprisingly, FSTL3 knockout mice are viable and have no obvious defects in embryonic development or perinatal growth. The defects seen in many regulator knockouts, along with possible functional redundancy between FST and FSTL3 suggest that extracellular regulators of TGF