Haploinsufficiency of hnRNP U Changes Activity Pattern and Metabolic Rhythms

Beibei Lai; Jianghuan Zou; Zhaoyu Lin; Zhipeng Qu; Anying Song; Ying Xu; Xiang Gao

doi:10.1016/j.ajpath.2017.09.017

Haploinsufficiency of hnRNP U Changes Activity Pattern and Metabolic Rhythms

Am J Pathol. 2018 Jan;188(1):173-183. doi: 10.1016/j.ajpath.2017.09.017. Epub 2017 Nov 9.

Authors

Beibei Lai¹, Jianghuan Zou¹, Zhaoyu Lin¹, Zhipeng Qu¹, Anying Song¹, Ying Xu², Xiang Gao³

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing, China.
² Medical College of Soochou University, Suzhou, China. Electronic address: xuying@nicemice.cn.
³ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing, China. Electronic address: gaoxiang@nju.edu.cn.

PMID: 29128567
DOI: 10.1016/j.ajpath.2017.09.017

Abstract

The neuropeptides arginine vasopressin (Avp) and vasoactive intestinal polypeptide (Vip) are critical for the communication and coupling of suprachiasmatic nucleus neurons, which organize daily rhythms of physiology and behavior in mammals. However, how these peptides are regulated remains uncharacterized. We found that heterogeneous nuclear ribonucleoprotein U (hnRNP U) is essential for the expression of Avp and Vip. Loss of one copy of the Hnrnpu gene resulted in fragmented locomotor activities and disrupted metabolic rhythms. Hnrnpu^+/- mice were more active than wild-type mice in the daytime but more inactive at night. These phenotypes were partially rescued by microinfusion of Avp and Vip into free-moving animals. In addition, hnRNP U modulated Avp and Vip via directly binding to their promoters together with brain and muscle Arnt-like protein-1/circadian locomotor output cycles kaput heterodimers. Our work identifies hnRNP U as a novel regulator of the circadian pacemaker and provides new insights into the mechanism of rhythm output.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arginine Vasopressin / genetics
Arginine Vasopressin / metabolism
Arginine Vasopressin / pharmacology
Circadian Rhythm / drug effects
Circadian Rhythm / genetics*
Female
Gene Expression Regulation
Haploinsufficiency
Heterogeneous-Nuclear Ribonucleoprotein U / genetics*
Male
Mice
Mice, Knockout
Motor Activity / drug effects
Motor Activity / genetics*
Vasoactive Intestinal Peptide / genetics
Vasoactive Intestinal Peptide / metabolism
Vasoactive Intestinal Peptide / pharmacology

Substances

Heterogeneous-Nuclear Ribonucleoprotein U
Arginine Vasopressin
Vasoactive Intestinal Peptide