ESPE Yearbook of Paediatric Endocrinology

Brief summary: Using human induced pluripotent stem cells as well as transgenic mouse models, this paper shows that MKRN3 could initiate pubertal onset by regulating hypothalamic development and plasticity.

The reactivation of GnRH secretion at puberty is thought to result from a loss in inhibitory input together with an increase in transactivation onto GnRH neurons. The main component of this inhibitory tone was incompletely understood until the discovery of Makorin ring finger protein 3 (MKRN3) loss-of-function mutations in patients with familial central precocious puberty (CPP). Such mutations are the most common cause of familial CPP (1, 2). Recent studies have started to decipher the role of MKRN3 in controlling pubertal timing.

MKRN3 is a ubiquitin ligase expressed in the mediobasal hypothalamus and the preoptic area. Its expression is high during embryonic life and sharply decreases before the onset of puberty (3). MKRN3 is expressed specifically in kisspeptin neurons and regulates KISS1 and TAC3 promoter activity. Overall, these data suggest that MKRN3 acts upstream of GnRH, at the level of kisspeptin and neurokinin B neurons to inhibit GnRH secretion before puberty.

These authors used human induced pluripotent stem cells differentiated into arcuate nucleus neurons to explore the mechanisms of action of MKRN3 in the hypothalamic control of puberty. MKRN3 was not expressed in iPSCs but became highly induced during hypothalamic differentiation. MKRN3 deletion in hypothalamic neurons resulted in significant changes in the expression of genes involved in axon guidance and synapse formation, suggesting a role in hypothalamic development and plasticity. Consistent with those results, MKRN3 deletion in a mouse model led to an increase in dendritic spines in the arcuate nucleus, but did not affect GnRH neuron morphology. MKRN3 deletion was associated with earlier first estrus in females and a milder phenotype of advanced puberty in males. Overall, the CPP phenotype was more moderate than in the previously published knock-out model obtained using TALEN technology (4). Mkrn3 deletion did not affect GnRH1, kiss1 or tac3 mRNA expression, but decreased neurokinin B protein expression, suggesting a post-transcriptional mechanism involved in the activation of GnRH secretion around puberty. The study also identified a potential new player in the control of puberty, as MKRN3 interacted with IGF2BP1 and decreased its protein expression in the arcuate nucleus. IGF2BP1 is known to be involved in mRNA translation.

In conclusion, this article brings significant new data supporting a potential role for MKRN3 in hypothalamic development.

References: 1. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, Kaiser UB. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013; 368(26):2467–2475. 2. Valadares LP, Meireles CG, De Toledo IP, Santarem de Oliveira R, Gonçalves de Castro LC, Abreu AP, Carroll RS, Latronico AC, Kaiser UB, Guerra ENS, Lofrano-Porto A. MKRN3 mutations in central precocious puberty: a systematic review and meta-analysis. J Endocr Soc. 2019; 3(5):979–995. 3. Abreu AP, Toro CA, Song YB, Navarro VM, Bosch MA, Eren A, Liang JN, Carroll RS, Latronico AC, Rønnekleiv OK, Aylwin CF, Lomniczi A, Ojeda S, Kaiser UB. MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. J Clin Invest. 2020 Aug 3;130(8):4486–4500. 4. Li C, Lu W, Yang L, Li Z, Zhou X, Guo R, Wang J, Wu Z, Dong Z, Ning G, Shi Y, Gu Y, Chen P, Hao Z, Han T, Yang M, Wang W, Huang X, Li Y, Gao S, Hu R. MKRN3 regulates the epigenetic switch of mammalian puberty via ubiquitination of MBD3. Natl Sci Rev.2020;7(3):671–685.