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| Status |
Public on Feb 13, 2023 |
| Title |
Altered GnRH neuron and ovarian innervation characterize reproductive dysfunction linked to the Fragile X messenger ribonucleoprotein (Fmr1) gene mutation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene cause Fragile X Syndrome, the most common monogenic cause of intellectual disability. Mutations of FMR1 are also associated with reproductive disorders, such as early cessation of reproductive function in females. While progress has been made in understanding the mechanisms of mental impairment, causes of reproductive disorders are not clear. FMR1-associated reproductive disorders were studied exclusively from the endocrine perspective, while FMR1 role in neurons that control reproduction was addressed. Here, we demonstrate that similar to women with FMR1 mutations, female Fmr1 null mice stop reproducing early. However, young null females display larger litters, more corpora lutea in the ovaries, increased inhibin, progesterone, testosterone, and gonadotropin hormones in the circulation. Given elevated ovarian hormones, increase in gonadotropins is not due to the lack of ovarian feedback, and ovariectomy reveals both hypothalamic and ovarian contribution to elevated gonadotropins. Increased vascularization of corpora lutea, higher sympathetic innervation of growing follicles in the ovaries of Fmr1 nulls, and higher numbers of synaptic GABAA receptors in GnRH neurons, which are excitatory for GnRH neurons, are also determined. Altered mRNA and protein levels of synaptic molecules in the hypothalamus are identified. Unmodified and ovariectomized Fmr1 nulls have increased LH pulse frequency, suggesting that Fmr1 nulls exhibit hyperactive GnRH neurons, regardless of ovarian feedback. These results reveal Fmr1 function in the regulation of GnRH neuron activity, and point to the role of GnRH neurons, in addition to the ovarian innervation, in the etiology of Fmr1-mediated reproductive disorders.
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| Overall design |
In this study, (WT female, Fmr1 KO female) were analyzed for hypothalmic gene expression changes by Nanostring. Gene expression in 50 ng RNA per sample was analyzed using the Nanostring instrument, according to manufacturer’s instruction, with the nCounter Mouse Neuroinflammation Panel (770 genes, gene list available at the manufacturer’s website). Panel was customized with an addition of 30 custom probes for hypothalamic neuropeptides and their receptors.
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| Contributor(s) |
Villa PA, Coss D |
| Citation(s) |
36909303 |
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| Submission date |
Jan 12, 2023 |
| Last update date |
May 15, 2023 |
| Contact name |
Djurdjica Coss |
| E-mail(s) |
djurdjica.coss@medsch.ucr.edu
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| Organization name |
UC Riverside
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| Department |
Biomedical Sciences
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| Lab |
Coss
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| Street address |
900 University Ave
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| City |
Riverside |
| State/province |
CA |
| ZIP/Postal code |
92521 |
| Country |
USA |
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| Platforms (1) |
| GPL33016 |
NanoString nCounter Mouse Neuroinflammation Panel |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA923271 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE222723_Nanostring_Fmr1_Female_RAW.xlsx |
66.5 Kb |
(ftp)(http) |
XLSX |
| Processed data included within Sample table |
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