Neuron-Specific Menin Deletion Leads to Synaptic Dysfunction and Cognitive Impairment by Modulating p35 Expression

Kai Zhuang, Changquan Huang, Lige Leng, Honghua Zheng, Yuehong Gao, Guimiao Chen, Zhilin Ji, Hao Sun, Yu Hu, Di Wu, Meng Shi, Huifang Li, Yingjun Zhao, Yunwu Zhang, Maoqiang Xue, Guojun Bu, Timothy Y. Huang, Huaxi Xu, Jie Zhang

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Menin (MEN1) is a critical modulator of tissue development and maintenance. As such, MEN1 mutations are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin is abundantly expressed in the nervous system, little is known with regard to its function in the adult brain. Here, we demonstrate that neuron-specific deletion of Men1 (CcKO) affects dendritic branching and spine formation, resulting in defects in synaptic function, learning, and memory. Furthermore, we find that menin binds to the p35 promoter region to facilitate p35 transcription. As a primary Cdk5 activator, p35 is expressed mainly in neurons and is critical for brain development and synaptic plasticity. Restoration of p35 expression in the hippocampus and cortex of Men1 CcKO mice rescues synaptic and cognitive deficits associated with Men1 deletion. These results reveal a critical role for menin in synaptic and cognitive function by modulating the p35-Cdk5 pathway. The biological function of menin in neurons remains unclear. Zhuang et al. report that menin regulates neuronal dendritic branching, spine density, and synaptic plasticity. Menin binds to the p35 promoter to enhance p35 transcription and CDK5 activity. The study demonstrates a role for menin in synaptic and cognitive function.

Original languageEnglish (US)
Pages (from-to)701-712
Number of pages12
JournalCell reports
Volume24
Issue number3
DOIs
StatePublished - Jul 17 2018

Keywords

  • Cdk5
  • cognition
  • menin
  • p35
  • synaptic function

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhuang, K., Huang, C., Leng, L., Zheng, H., Gao, Y., Chen, G., Ji, Z., Sun, H., Hu, Y., Wu, D., Shi, M., Li, H., Zhao, Y., Zhang, Y., Xue, M., Bu, G., Huang, T. Y., Xu, H., & Zhang, J. (2018). Neuron-Specific Menin Deletion Leads to Synaptic Dysfunction and Cognitive Impairment by Modulating p35 Expression. Cell reports, 24(3), 701-712. https://doi.org/10.1016/j.celrep.2018.06.055