Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2020-08, Vol.130 (8), p.4486-4500

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.