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NIH grant 1R01HD121678-01: Mechanisms and Therapeutic Potential of MKRN3 in the Neuroendocrine Regulation of Puberty and Reproduction
Institute: {'code': 'HD', 'abbreviation': 'NICHD', 'name': 'Eunice Kennedy Shriver National Institute of Child Health and Human Development', 'admin_org_id': '12500030', 'admin_funding_url': ''}. PI: Stephanie Anne Roberts. Award: $692296.
Start: 2026-09-05T00:00:00.
PROJECT SUMMARY
The precise neuroendocrine mechanisms governing pubertal onset and maintenance of reproduction remain to
be fully elucidated. Puberty is controlled by the hypothalamic-pituitary-gonadal axis, which reactivates in
adolescence through pulsatile GnRH secretion activated by upstream kisspeptin neurons, which co-express
kisspeptin, neurokinin B, and dynorphin (KNDy), in the arcuate nucleus of the hypothalamus (ARC). GnRH
secretion stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to
gonadal steroid production. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most
common genetic cause of central precocious puberty (CPP), and population studies implicate MKRN3 in pubertal
timing in association with the age of menarche in women. In mice, hypothalamic Mkrn3 expression is high early
in life and declines prior to puberty, suggesting a key inhibitory role. Mkrn3 deficiency advances pubertal onset
in female mice and increases neurokinin B expression in the ARC, and conversely, our prior work demonstrates
that neonatal hypothalamic Mkrn3 overexpression delays puberty in female mice and reduces neurokinin B and
kisspeptin protein expression in the ARC. These findings support MKRN3 as a central inhibitor of KNDy neurons.
We have recently generated a novel mouse model with targeted Mkrn3 overexpression in kisspeptin neurons,
which also show delayed pubertal onset, and propose to harness MKRN3’s inhibitory effects as a potential future
therapeutic strategy for CPP and polycystic ovary syndrome (PCOS), disorders characterized by premature and
dysregulated KNDy neuron activity, respectively. We will investigate whether targeted Mkrn3 overexpression in
kisspeptin neurons can normalize pubertal timing in a mouse model of early pubertal timing, and use single-cell
spatial transcriptomics to delineate MKRN3’s targets in the ARC in this model. We will also study whether Mkrn3
overexpression in kisspeptin neurons ameliorates a PCOS-like phenotype in a mouse model, hypothesizing that
MKRN3 will suppress the elevated LH pulse frequency characteristic of PCOS in women. Finally, in addition to
its important mechanism of action in KNDy neurons, in vivo and in vitro studies suggest MKRN3 may also have
direct inhibitory effects on GnRH neurons, however, this has not been fully investigated. Therefore, we propose
to generate mice with selective Mkrn3 overexpression in GnRH neurons to determine whether MKRN3 also
directly inhibits GnRH neuronal activation and secretion, and we hypothesize this will manifest as delayed
puberty in mice. In humans, pubertal and reproductive disorders can also have implications for other short and
long-term health risks such as psychosocial distress, metabolic syndrome, cardiovascular disease, and cancer.
By elucidating MKRN3’s mechanisms and therapeutic potential, our work aims to fill critical gaps in the
understanding and treatment of pubertal and reproductive disorders, ultimately advancing the health of children
and women.document fetched 2026-09-13 02:45