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Comment |
ROLE AND REGULATION OF NODAL/ALK7 SIGNALING PATHWAY IN THE CONTROL OF OVARIAN FOLLICULAR ATRESIA. Wang H et al. Although the role of the transforming growth factor (TGF) beta superfamily members in the regulation of ovarian folliculogenesis has been extensively studied, their involvement in follicular atresia is not well understood. In the present study, we have demonstrated for the first time that Nodal, a member of the TGF beta superfamily, is involved in promoting follicular atresia as evidenced by: (a) Co-localization of Nodal and its type I receptor ALK7 proteins in the granulosa cells was only observed in atretic antral follicles, while they were present in theca cells and granulosa cells of healthy follicles, respectively; (b) Addition of recombinant Nodal or over-expression of Nodal by adenoviral infection induced apoptosis of otherwise healthy granulosa cells; (c) Constitutively active ALK7 (ALK7-ca) over-expression mimicked the function of Nodal in the induction of granulosa cell apoptosis. Furthermore, over-expression of Nodal or ALK7-ca increased phosphorylation and nuclear translocation of Smad2, decreased Xiap expression at both mRNA and protein level and phospho-Akt content, as well as triggered mitochondrial release of death proteins Smac/DIABLO, Omi/HtrA2 and cytochrome c in the granulosa cells. Dominant negative-Smad2 significantly attenuated ALK7-ca-induced down-regulation of Xiap and thus rescued granulosa cells from undergoing apoptosis. In addition, while up-regulation of Xiap significantly attenuated ALK7-ca-induced apoptosis, down-regulation of Xiap sensitized granulosa cells to ALK7-ca-induced apoptosis. Furthermore, ALK7-ca-induced apoptosis was significantly attenuated by forced expression of activated Akt, and Akt rescued granulosa cells from undergoing apoptosis via proteasome-mediated ALK7 degradation. Taken together, Nodal plays an atretogenic role in the ovary where it induces granulosa cell apoptosis through activation of Smad2, down-regulation of the key survival molecules Xiap and phospho-Akt, as well as the activation of mitochondrial death pathway.
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Mutations |
1 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Neuroendocrine control of female reproductive function by the activin receptor ALK7. Sandoval-Guzmn T et al. 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.-Sandoval-Guzmn, T., Gngrich, C., Moliner, A., Guo, T., Wu, H., Broberger, C., Ibez, C. F. Neuroendocrine control of female reproductive function by the activin receptor ALK7.
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