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GDF9 modulates the reproductive and tumor phenotype of female inha-null mice.

ABSTRACT: Intraovarian factors play important roles in coordinating germ cell and somatic cell growth in the ovary. Prior to the onset of gonadotropin stimulation and reproductive cyclicity, follicle development is dependent upon locally produced growth factors, such as the transforming growth factor beta family members inhibin, activin, and GDF9. In the absence of inhibin in prepubertal mice (Inha(-/-)), there are marked alterations in preantral follicle growth, but no evidence of ovarian tumors characteristic of adult Inha-null mice. To ascertain the contribution of GDF9 to the Inha-null phenotype, we analyzed folliculogenesis in postnatal Inha Gdf9 double knockout mice. Deletion of Gdf9 from Inha(-/-) rescues the initial growth defects found at early follicle stages in Inha(-/-) ovaries, but surprisingly enhances the onset of pretumor lesions. The normalization of growth dynamics between granulosa cells and oocytes of Inha Gdf9 double knockout mice is also accompanied by a reduction in levels of the activin/inhibin beta B subunit, Inhbb, which is upregulated in Inha(-/-) ovaries. However, at later ages, Inha Gdf9 double knockout ovaries are similar to Inha(-/-) ovaries, and show upregulation of the activin/inhibin subunits and downregulation of the growth factor, kit ligand, thus resulting in a local environment that is growth-promoting for granulosa cells but growth-inhibitory for oocytes. These data suggest a sequential mechanism of action initiated by GDF9 in the Inha knockout mouse that promotes defective folliculogenesis. These studies thus provide a novel role for GDF9 in causing reproductive defects and suppressing tumor initiation in the Inha(-/-) mouse model.

SUBMITTER: Myers M

PROVIDER: S-EPMC4013870 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

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GDF9 modulates the reproductive and tumor phenotype of female inha-null mice.

Myers Michelle M Mansouri-Attia Nadera N James Rebecca R Peng Jia J Pangas Stephanie A SA

Biology of reproduction 20130404 4

Intraovarian factors play important roles in coordinating germ cell and somatic cell growth in the ovary. Prior to the onset of gonadotropin stimulation and reproductive cyclicity, follicle development is dependent upon locally produced growth factors, such as the transforming growth factor beta family members inhibin, activin, and GDF9. In the absence of inhibin in prepubertal mice (Inha(-/-)), there are marked alterations in preantral follicle growth, but no evidence of ovarian tumors characte ...[more]

PMID: 23446452

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Project description:Genetic modifier screens provide a useful tool, in diverse organisms from Drosophila to C. elegans and mice, for recovering new genes of interest that may reduce or enhance a phenotype of interest. This study reports a modifier screen, based on N-ethyl-N-nitrosourea (ENU) mutagenesis and outcrossing, designed to increase understanding of the normal function of murine α-synuclein ( Snca ). Human SNCA was the first gene linked to familial Parkinson's disease. Since the discovery of the genetic link of SNCA to Parkinson's nearly three decades ago, numerous studies have investigated the normal function of SNCA protein with divergent roles associated with different cellular compartments. Understanding of the normal function of murine Snca is complicated by the fact that mice with homozygous null mutations live a normal lifespan and have only subtle synaptic deficits. Here, we report that the first genetic modifier (a sensitized mutation) that was identified in our screen was the X-linked gene, ATPase copper transporting alpha (Atp7a). In humans, mutations in Atp7a are linked to to Menkes disease, a disease with pleiotropic phenotypes that include a severe neurological component. Atp7a encodes a trans-Golgi copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network. Male mice that carry a mutation in Atp7a die within 3 weeks of age regardless of Snca genotype. In contrast, here we show that Snca disruption modifies the phenotype of Atp7a in female mice. Female mice that carry the Atp7a mutation, on an Snca null background, die earlier (prior to 35 days) at a significantly higher rate than those that carry the Atp7a mutation on a wildtype Snca background ATPase copper transporting alpha. Thus, Snca null mutations sensitize female mice to mutations in Atp7a, suggesting that Snca protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. Although data has suggested diverse functions for human and mouse α-synuclein proteins in multiple cell compartments, this is the first demonstration via use of genetic screening to demonstrate that Snca protein may function in the ER-Golgi system in the mammalian brain in a sex-dependent manner.Author summaryThis study sought to probe the normal function(s) of a protein associated with Parkinson's disease, the second most common neurodegenerative disease in humans. We used a genetic modifier approach to uncover aspects of normal protein function, via mutagenesis of mice and screening for neurological problems that are decreased or enhanced in mice that are null for α-synuclein ( Snca) . Through these studies, we identified the X-linked gene that is mutated in Menkes disease in humans as a modifier of the null Snca phenotype, specifically in female mice. The gene mutated in Menkes disease, ATP7a , encodes a copper transporter that is known to act in the trans-Golgi sub-cellular compartment. Genetic modifier effects suggest that Snca may also play a role in that compartment, potentially in the mammalian brain.

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GDF9 modulates the reproductive and tumor phenotype of female inha-null mice.

Publications

GDF9 modulates the reproductive and tumor phenotype of female inha-null mice.

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