MKRN3 inhibits puberty onset via interaction with IGF2BP1 and regulation of hypothalamic plasticity

Area of Science:

• Neuroendocrinology
• Developmental Biology
• Genetics

Background:

• Makorin ring finger protein 3 (MKRN3) is implicated as a puberty inhibitor, with loss-of-function mutations linked to central precocious puberty.
• Prepubertal downregulation of Mkrn3 expression in the mouse hypothalamus supports its inhibitory role in puberty onset.

Purpose of the Study:

• To elucidate the mechanisms by which MKRN3 regulates the central control of puberty initiation.
• To investigate the impact of MKRN3 deletion on hypothalamic development, plasticity, and key neuroendocrine pathways.

Main Methods:

• Utilized human induced pluripotent stem cell-derived hypothalamic neurons to assess MKRN3's role in gene expression.
• Employed a mouse model with Mkrn3 deletion to study effects on puberty onset, neuroanatomy, and neuroendocrine signaling.
• Performed proteomics and interactome analysis to identify MKRN3 targets, including NKB and IGF2BP1.

Main Results:

• MKRN3 deletion in human iPSC-derived neurons altered genes controlling hypothalamic development and plasticity.
• Mkrn3 deletion in mice resulted in accelerated puberty onset in females and increased dendritic spine density in the arcuate nucleus.
• Identified neurokinin B (NKB) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as direct or indirect targets of MKRN3.

Conclusions:

• MKRN3 inhibits pubertal initiation by regulating prepubertal hypothalamic development and plasticity.
• MKRN3 exerts its function partly through modulation of NKB and IGF2BP1 pathways.
• These findings reveal novel mechanisms underlying the central regulation of puberty onset involving MKRN3.