Mutations of the Fragile X messenger ribonucleoprotein 1 gene (Fmr1) — a leading genetic cause of intellectual impairment and autism — contribute to premature ovarian failure (POF) due to changes in neurons that regulate reproduction in the brain and ovaries, according to a study recently published in Frontiers in Endocrinology.
Researchers led by Djurdjica Coss, PhD, a professor of biomedical sciences at the University of California, Riverside School of Medicine, point out that FMR1 gene mutations are also associated with reproductive disorders, such as early menopause in females, and macroorchidism in males, and while the effect of FMR1 mutations on the cortex and hippocampus have been analyzed, how mutations affect hypothalamic functions have not been examined. “Given that Fmr1 gene mutations are also associated with reproductive disorders, combined with increasing infertility rates, it is critical to examine Fmr1 role in the reproductive axis,” the authors write.
For this study, researchers used transgenic mice that lack the Fmr1 gene to emulate the condition in people with a mutation in this gene. They first determined that this mouse model mimics what is observed in women with a Fmr1 mutation, and then compared the reproduction-regulating neurons in the ovaries and the brain between these mice and their normal counterparts. Coss and her team found the changes in function of these neurons led to a more rapid secretion of hormones in young transgenic female mice that later stopped reproducing early.
The researchers then removed the ovaries from these mice to determine the effect of the Fmr1 mutation on just the neurons in the brain, finding that gonadotropin-releasing hormone (GnRH) neurons showed changes in connectivity that affect how they function, with an increased number of synapses that cause them to be faster and have more pulses of hormone secretion. The team also determined that neurons supplying the ovaries with nerves were more abundant in the transgenic mice than in their normal counterparts.
“These results reveal Fmr1 function in the regulation of GnRH neuron secretion, and point to the role of GnRH neurons, in addition to the ovarian innervation, in the etiology of Fmr1-mediated reproductive disorders,” the authors conclude.