Neuroendocrine control of female reproductive function by the activin receptor ALK7

Abstract

Activins are critical components of the signaling network that controls female reproduction. However, their roles in hypothalamus, and the specific functions of their different receptors, have not been elucidated. Here, we investigated the expression and function of the activin receptor ALK7 in the female reproductive axis using Alk7-knockout mice. ALK7 was found in subsets of SF1-expressing granulosa cells in the ovary, FSH gonadotrophs in the pituitary, and NPY-expressing neurons in the arcuate nucleus of the hypothalamus. Alk7-knockout females showed delayed onset of puberty and abnormal estrous cyclicity, had abnormal diestrous levels of FSH and LH in serum, and their ovaries showed premature depletion of follicles, oocyte degeneration, and impaired responses to exogenous gonadotropins. In the arcuate nucleus, mutant mice showed reduced expression of Npy mRNA and lower numbers of Npy-expressing neurons than wild-type controls. Alk7 knockouts showed a selective loss of arcuate NPY/AgRP innervation in the medial preoptic area, a key central regulator of reproduction. These results indicate that ALK7 is an important regulator of female reproductive function and reveal a new role for activin signaling in the control of hypothalamic gene expression and wiring. Alk7 gene variants may contribute to female reproductive disorders in humans, such as polycystic ovary syndrome.

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

“…The relative importance of these receptors is presently unclear and may be ligand specific, because activin B and AB can engage both receptors, whereas activin A only signals via ACVR1B (27,28). Notably, activin A or B induction of FSH secretion is preserved in cultured pituitaries of Acvr1c knockout mice, suggesting that ACVR1B may be the preferred type I receptor, or that it can compensate for the loss of ACVR1C (29).…”

“…None of the treatments affected Gnrhr mRNA levels, suggesting that receptor expression is independent of activin signaling, at least in culture and under these experimental conditions. receptors, ACVR1C, show normal basal and activin Bstimulated FSH release in culture (29). Thus, either activin B is not the primary ligand driving FSH synthesis in vivo, or there are additional ligands that compensate in its absence or act redundantly.…”

Gonadotropes and Gonadotropin-Releasing Hormone Signaling

“…Activin signaling via ACVR2 (the type II receptor) occurs in collaboration with the type I receptors ALK4 and/or ALK7 in gonadotropes [505][506][507][508] ; however, it appears that ALK4 may have higher importance in activin signaling based upon pharmacological studies in LβT2 cells and the ALK7 knockout mouse. 170 Activin engagement of the activin receptor complex results in rapid phosphorylation of SMAD2 and SMAD3, followed by nuclear localization of SMAD2/3 and SMAD4 complexes in LβT2 cells.…”

Follicular Development

“…However, Alk7 knockout mice are viable. 434 Alk7 is also expressed in gonadotropes of the pituitary as well as some neurons of the neuroendocrine hypothalamus. 434 Alk7 is also expressed in gonadotropes of the pituitary as well as some neurons of the neuroendocrine hypothalamus.…”

“…433 In the ovary, Alk7 is expressed in steroidogenic factor 1 (SF1, also called Nr5a1)-positive granulosa cells. 434 Female mice null for Alk7 (Alk7 −/− ) have a delayed reproductive cycle, although the phenotype is complicated due to the expression pattern in multiple reproductive tissues. 434 Female mice null for Alk7 (Alk7 −/− ) have a delayed reproductive cycle, although the phenotype is complicated due to the expression pattern in multiple reproductive tissues.…”