Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation.

Huifang Liu,Xiangxin Kong,Fengling Chen

doi:10.18632/oncotarget.19347

Abstract

Central precocious puberty (CPP) is attributed to the disorder of some trigger factors those can activate the hypothalamic-pituitary-gonadal axis controlled by GnRH neurons. Many recent studies reveal one of those trigger factors, Makorin ring finger protein 3 (Mkrn3), whose loss-of-function mutations are implicated in CPP. Although Mkrn3 contained zinc Ring finger domain is considered as a putative E3 ubiquitin ligase, its actual function is never reported. Here, our results demonstrated that in mice hypothalamus before and when puberty initiated, Mkrn3 expressed the reversed tendency with Nptx1, which is an important secreted protein for neuron development. Furthermore, our data manifested that Mkrn3 interacted and suppressed Nptx1 activity. And the Ring finger domain of Mkrn3 contained was determined to be essential for binding with Nptx1 for its polyubiquitination during the puberty initiation. Our study shed light on the molecular insights into the function of Mkrn3 in the events of puberty initiation.

Highlights

Puberty is the physiological transition stage between childhood to adulthood
To validate the expressed pattern of Makorin ring finger protein 3 (Mkrn3) and neural pentraxin-1 precursor (Nptx1) in hypothalamus, the expression of these two endogenous proteins were investigated in the whole tissue lysis of hypothalamus of 4, 6- and 10- week old female mice (Figure 1, Supplementary Figure 2)
We observed Mkrn3 was sharply reduced in 6- and 10- compared to 4-week old hypothalamus, which was consistent with previous studies that Mkrn3 disappears after puberty initiates [12]

Summary

Introduction

From the aspect of neuroendocrine, the enhanced and sustained pulsatile release of gonadotropinreleasing hormone (GnRH) in hypothalamus activates the hypothalamic-pituitary-gonadal axis and contributes to mammalian puberty initiation. The premature reactivation of this axis at the inappropriate chronological age results in central precocious puberty (CPP) [1]. Nutritional and environmental factors driven by GnRH construct a complex interaction network and play a crucial role in determining the onset of puberty. The studies on the neuroendocrine mechanisms of CPP provided the evidence of stimulatory or inhibitory effect on GnRH neurons governed by many genes [2]. Recent studies have been conducted to explore the genetic causes for CPP [3,4,5]. Further functions of those GnRH targets were still less studied

Methods

Results

Conclusion