title: 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.
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Sandoval-Guzmán
authors.forename: Christina
authors.initials: C
authors.lastname: Göngrich
authors.forename: Annalena
authors.initials: A
authors.lastname: Moliner
authors.forename: Tingqing
authors.initials: T
authors.lastname: Guo
authors.forename: Haiya
authors.initials: H
authors.lastname: Wu
authors.forename: Christian
authors.initials: C
authors.lastname: Broberger
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Ibáñez
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030762:Estrous Cycle / Q000235:genetics / Q000502:physiology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009490:Neurosecretory Systems / Q000378:metabolism; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000378:metabolism*; D012098:Reproduction / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012741:Sexual Maturation / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D009478:Neuropeptide Y; D049452:Green Fluorescent Proteins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D030201:Activin Receptors, Type I; C515277:Acvr1c protein, mouse