MKRN3 Overexpression in Female Mice Disrupts Reproductive Hormone Axis

MKRN3 (Makorin Ring Finger Protein 3) is a critical regulator of puberty onset, with its mutations often leading to central precocious puberty. While its role in initiating puberty is well-established, how its overexpression impacts the hypothalamic-pituitary-gonadal (HPG) axis, the central regulator of reproduction, in already postpubertal females remains poorly understood.

The study revealed that MKRN3 overexpression significantly altered the HPG axis in postpubertal female mice. Treated mice exhibited a substantial 35% reduction in circulating luteinizing hormone (LH) levels compared to controls (p<0.001) and a 28% decrease in follicle-stimulating hormone (FSH) levels (p<0.005) by week 4. These hormones are crucial for ovarian function. The most striking finding was a 50% decrease in ovarian follicle count and a 60% reduction in ovulation rates in the MKRN3 overexpression group compared to controls (p<0.001), indicating severe reproductive impairment. Furthermore, estradiol levels were down by 40% (p<0.01), and progesterone levels showed a 30% decrease (p<0.05) in the treated group by week 6, reflecting significant gonadal dysfunction. Gene expression analysis in the hypothalamus revealed a 2.5-fold increase in Kiss1 mRNA (a neuropeptide crucial for GnRH secretion) and a 1.8-fold decrease in GnRH mRNA (gonadotropin-releasing hormone, which stimulates LH and FSH release) in the MKRN3 group, suggesting complex central regulatory changes.