MiR-664-2 impacts pubertal development in a precocious-puberty rat model through targeting the NMDA receptor-1†

Abstract

Precocious puberty (PP) commonly results from premature activation of the hypothalamic–pituitary–gonadal axis (HPGA). Gonadotropin-releasing hormone (GnRH) is the initial trigger for HPGA activation and plays an important role in puberty onset. N-methyl-D-aspartate (NMDA) can promote pulsatile GnRH secretion and accelerates puberty onset. However, the mechanism of N-methyl-D-aspartate receptors (NMDARs) in PP pathogenesis remains obscure. We found that serum GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen (E2) levels, hypothalamic NMDAR1, and GnRH mRNA expression peaked at the vaginal opening (VO) day. Next, the hypothalamic NMDAR1 mRNA and protein levels in rats treated with danazol, a chemical commonly effecting on the reproductive system, were significantly increased at the VO day (postnatal day 24) compared to controls, accompanied by enhanced serum GnRH, LH, FSH, and E2 levels. Further, microRNA-664-2 (miR-664-2) was selected after bioinformatics analysis and approved in primary hypothalamic neurons, which binds to the 3′-untranslated regions of NMDAR1. Consistently, the miR-664-2 expression in hypothalamus of the Danazol group was decreased compared to Vehicle. Our results suggested that attenuated miR-664-2 might participate in PP pathogenesis through enhancing the NMDAR1 signaling.

Precocious Puberty and Covid-19 Into Perspective: Potential Increased Frequency, Possible Causes, and a Potential Emergency to Be Addressed

“…A further consideration is that if the hypotheses above are correct, considering psychological distress, and the changes in diet including overeating during the pandemic, changes in DNA methylation, in the microRNA network and in the microbiota must also be taken into account. If this were the case in the next years these changes would determine an increase in ovarian dysfunction as polycystic ovary syndrome too (22,23) that would need to be carefully monitored. Related with the current above aspects are reports of early puberty in girls born with a low birth weight but with subsequent rapid catch-up growth and subsequent increase in visceral fat as they often present an acceleration of puberty and an increased risk of polycystic ovary syndrome (24).…”

The Reason of Increasing Puberty Precocious Cases During the Pandemic Period: Obesity or Not?

“…Values represent median (minimum-maximum) described (17). And all of these factors may affect the mediators and signaling pathways involved in the onset of puberty.…”

Pubertal orchestration of hormones and testis in primates

“…The intermittent stimulation of the hypothalamus with neuro-chemical N-methyl-D-aspartate (NMDA, an agonist of Glutamate) in male juvenile rhesus monkeys was first reported to drive the pituitary-testicular axis into the pubertal mode in a GnRH dependent manner (Plant, Gay, Marshall, & Arslan, 1989). A recent study has provided support to this by demonstrating the role of microRNA Mir-664-2 in precocious puberty pathogenesis by regulating the expression of NMDA receptor-1 in rats (Ju et al, 2019). Pulsatile GnRH infusion (0.1-0.3 μg GnRH pulse over 2 min/3 hr) to juvenile monkeys for 4-5 weeks causes the onset of puberty-like maturation in the HPT axis with the precocious onset of spermatogenesis (Majumdar, Sarda, Bhattacharya, & Plant, 2012;Majumdar et al, 1995).…”