MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons
| Autor: | Carlos F. Aylwin, Ana Paula Abreu, Ursula B. Kaiser, Sergio R. Ojeda, Yong Bhum Song, Víctor M. Navarro, Carlos A. Toro, Joy N. Liang, Ana Claudia Latronico, Aysegul Eren, Alejandro Lomniczi, Rona S. Carroll, Oline K. Rønnekleiv, Martha A. Bosch |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Transcription Genetic Neurokinin B Ubiquitin-Protein Ligases Central precocious puberty Puberty Precocious Biology Gonadotropin-Releasing Hormone Rats Sprague-Dawley Mice Basal (phylogenetics) 03 medical and health sciences 0302 clinical medicine Kisspeptin Arcuate nucleus Transcription (biology) Internal medicine medicine Animals Humans In patient Secretion Promoter Regions Genetic Neurons Kisspeptins Arcuate Nucleus of Hypothalamus General Medicine RING finger domain HEK293 Cells 030104 developmental biology Endocrinology Gene Expression Regulation Hypothalamus 030220 oncology & carcinogenesis Commentary Female hormones hormone substitutes and hormone antagonists Hormone |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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