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Hypothalamic Kisspeptin Neurons as a Target for Whole-Cell Patch-Clamp Recordings
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MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons

Ana Paula Abreu1, Carlos A Toro2, Yong Bhum Song1

  • 1Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The Journal of Clinical Investigation
|May 15, 2020
PubMed

Insights

Makorin 3 (MKRN3) acts as a crucial brake on puberty by suppressing the secretion of gonadotropin-releasing hormone (GnRH). Loss-of-function mutations in MKRN3 are linked to central precocious puberty, indicating its role in preventing early sexual maturation.

Area of Science:

  • Neuroendocrinology
  • Molecular Biology
  • Genetics

Background:

  • Loss-of-function mutations in MKRN3 are associated with central precocious puberty.
  • MKRN3 expression decreases in the hypothalamus before puberty onset in mice.
  • MKRN3 is hypothesized to act as a brake on gonadotropin-releasing hormone (GnRH) secretion.

Purpose of the Study:

  • To investigate the mechanism by which MKRN3 prevents premature puberty.
  • To elucidate the role of MKRN3 in regulating GnRH secretion.

Main Methods:

  • Examined MKRN3 expression patterns in the hypothalamus of rats and nonhuman primates.
  • Investigated the localization of Mkrn3 expression in mouse Kiss1 neurons.
  • Assessed the effect of MKRN3 on KISS1 and TAC3 promoter activity.
  • Determined MKRN3's ubiquitinase activity and the impact of mutations on this activity and gene repression.

Main Results:

  • MKRN3 expression is high early in life, decreases before puberty, and is sex steroid-independent in rats and nonhuman primates.
  • MKRN3 is expressed in mouse hypothalamic arcuate nucleus Kiss1 neurons.
  • MKRN3 represses KISS1 and TAC3 promoter activity, key stimulators of GnRH secretion.
  • MKRN3 possesses ubiquitinase activity, which is impaired by mutations affecting the RING finger domain, compromising its ability to repress KISS1 and TAC3.

Conclusions:

  • MKRN3 acts to prevent puberty initiation by repressing KISS1 and TAC3 transcription.
  • This repressive action may involve an MKRN3-directed ubiquitination mechanism.
  • MKRN3 functions as a key regulator of the timing of puberty onset.
Keywords:
EndocrinologySex hormones

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