MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons

The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty in association with the decrease in MKRN3 expression in the medial basal hypothalamus of mice before the initiation of reproductive maturation suggests that MKRN3 is acting as a brake on gonadotropi...

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Bibliographic Details
Published in:The Journal of clinical investigation 2020-08, Vol.130 (8), p.4486-4500
Main Authors: Abreu, Ana Paula, Toro, Carlos A, Song, Yong Bhum, Navarro, Victor M, Bosch, Martha A, Eren, Aysegul, Liang, Joy N, Carroll, Rona S, Latronico, Ana Claudia, Rønnekleiv, Oline K, Aylwin, Carlos F, Lomniczi, Alejandro, Ojeda, Sergio, Kaiser, Ursula B
Format: Article
Language:English
Subjects:
Age
Animals
Arcuate nucleus
Arcuate Nucleus of Hypothalamus - metabolism
Arcuate Nucleus of Hypothalamus - pathology
Biomedical research
Children
Female
Gene Expression Regulation
Gonadotropin-releasing hormone
Gonadotropin-Releasing Hormone - genetics
Gonadotropin-Releasing Hormone - metabolism
Gonadotropins
HEK293 Cells
Humans
Hypothalamus
Hypothalamus (medial)
Kiss1 protein
Kisspeptins - biosynthesis
Kisspeptins - genetics
Male
Mice
Mutation
Nervous system
Neurokinin B - genetics
Neurokinin B - metabolism
Neurons
Neurons - metabolism
Neurons - pathology
Pituitary (anterior)
Pituitary hormones
Promoter Regions, Genetic
Proteins
Puberty
Puberty, Precocious - genetics
Puberty, Precocious - metabolism
Puberty, Precocious - pathology
Rats, Sprague-Dawley
Rodents
Secretion
Steroid hormones
Transcription
Transcription, Genetic
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Description
Summary:The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty in association with the decrease in MKRN3 expression in the medial basal hypothalamus of mice before the initiation of reproductive maturation suggests that MKRN3 is acting as a brake on gonadotropin-releasing hormone (GnRH) secretion during childhood. In the current study, we investigated the mechanism by which MKRN3 prevents premature manifestation of the pubertal process. We showed that, as in mice, MKRN3 expression is high in the hypothalamus of rats and nonhuman primates early in life, decreases as puberty approaches, and is independent of sex steroid hormones. We demonstrated that Mkrn3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and that MKRN3 repressed promoter activity of human KISS1 and TAC3, 2 key stimulators of GnRH secretion. We further showed that MKRN3 has ubiquitinase activity, that this activity is reduced by MKRN3 mutations affecting the RING finger domain, and that these mutations compromised the ability of MKRN3 to repress KISS1 and TAC3 promoter activity. These results indicate that MKRN3 acts to prevent puberty initiation, at least in part, by repressing KISS1 and TAC3 transcription and that this action may involve an MKRN3-directed ubiquitination-mediated mechanism.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/jci136564