Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jul 18;8(49):85102-85109.
doi: 10.18632/oncotarget.19347. eCollection 2017 Oct 17.

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

Huifang Liu  1 , Xiangxin Kong  1 , Fengling Chen  1
Affiliations

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

Huifang Liu et al. Oncotarget. .

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.

Keywords: Mkrn3; Nptx1; hypothalamus; puberty; ubiquitination.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST We declare no conflicts of interest in this study.

Figures

Figure 1
Figure 1. The expression of Mkrn3 and Nptx1 in hypothalamus of 4-, 6- and 10-week old female mice
Figure 2
Figure 2. The interaction between Mkrn3 and Nptx1 in hypothalamus
Figure 3
Figure 3. Ring finger of Mkrn3 essential for interaction with Nptx1
Figure 4
Figure 4. The interaction domain between Mkrn3 and Nptx1
(A) The homology modeling of the Ring finger of Mkrn3 (Upper) and molecular docking with Mkrn3 and Nptx1 (Bottom). Green and red cartoon represent Mkrn3 and Nptx1 respectively. Sphere is for highlighting the interacted domain of Mkrn3. (B) The interacted domain of Nptx1 with Mkrn3 confirmed by IP. (C) The regulatory effect of Ring finger domain of Mkrn3 on Nptx1.
Figure 5
Figure 5. The polyubiquitination modification of Nptx1 by Mkrn3
(A) The polyubiquitination of Nptx1 in hypothalamus of 4-, 6- and 10-week old female mice. (B) The polyubiquitination of Nptx1 in 4-week old mice treated by wtMkrn3 and mtMkrn3 via lateral cerebroventricular administration.
See this image and copyright information in PMC

References

    1. Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol. 2016;4:265–274. - PubMed
    1. Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol. 2016;4:254–264. - PMC - PubMed
    1. Zhou SS, Li P. Effects of NELL2 on the regulation of GnRH expression and puberty in female rats. Genet Mol Res. 2014;13:6672–6682. - PubMed
    1. Xu J, Li P. Expression of EAP1 and CUX1 in the hypothalamus of female rats and relationship with KISS1 and GnRH. Endocr J. 2016;63:681–690. - PubMed
    1. Cukier P, Wright H, Rulfs T, Silveira LF, Teles MG, Mendonca BB, Arnhold IJ, Heger S, Latronico AC, Ojeda SR, Brito VN. Molecular and gene network analysis of thyroid transcription factor 1 (TTF1) and enhanced at puberty (EAP1) genes in patients with GnRH-dependent pubertal disorders. Horm Res Paediatr. 2013;80:257–266. - PubMed

LinkOut - more resources