@article{0078497207d34f00bcbe35145e482a2c,
title = "Neuron-Specific Menin Deletion Leads to Synaptic Dysfunction and Cognitive Impairment by Modulating p35 Expression",
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.",
keywords = "Cdk5, cognition, menin, p35, synaptic function",
author = "Kai Zhuang and Changquan Huang and Lige Leng and Honghua Zheng and Yuehong Gao and Guimiao Chen and Zhilin Ji and Hao Sun and Yu Hu and Di Wu and Meng Shi and Huifang Li and Yingjun Zhao and Yunwu Zhang and Maoqiang Xue and Guojun Bu and Huang, {Timothy Y.} and Huaxi Xu and Jie Zhang",
note = "Funding Information: We thank Prof. Guanghui Jin (Xiamen University) and Prof. Xianxin Hua (University of Pennsylvania) for sharing the Men1-floxp mice, Prof. Zengqiang Yuan for sharing the Nestin-Cre and CamKIIα-Cre mice, and BrainVTA for generating AAV. This work was supported by The National Natural Science Foundation of China (grants 81522016 , 31571055 , and 81271421 to J.Z.; grants 81100842 and 81771164 to H.Z.; and grants 81771163 and U1405222 to H.X.); the Fundamental Research Funds for the Central Universities (grants 20720150062 and 20720180049 to J.Z.); the Natural Science Foundation of Fujian Province of China (grants 2013J01147 and 2014J06019 to J.Z; grant 2014J01375 to M.X.; and grant 2016J01411 to H.Z.); and the National Key Research and Development Program of China (grant 2016YFC1305903 ). This work was also supported by the Program for New Century Excellent Talents in University (China) (NCET-13-0508 to J.Z.) and by grants from the NIH ( R21 AG059217 to T.Y.H. and R21 AG048519 , R01 AG021173 , R01 AG038710 , R01 AG044420 , R01 NS046673 , RF1 AG056130 , and RF1 AG056114 to H.X.), as well as from the Tanz Family Fund (to H.X.) and the Cure Alzheimer's Fund (to H.X.). Funding Information: We thank Prof. Guanghui Jin (Xiamen University) and Prof. Xianxin Hua (University of Pennsylvania) for sharing the Men1-floxp mice, Prof. Zengqiang Yuan for sharing the Nestin-Cre and CamKII?-Cre mice, and BrainVTA for generating AAV. This work was supported by The National Natural Science Foundation of China (grants 81522016, 31571055, and 81271421 to J.Z.; grants 81100842 and 81771164 to H.Z.; and grants 81771163 and U1405222 to H.X.); the Fundamental Research Funds for the Central Universities (grants 20720150062 and 20720180049 to J.Z.); the Natural Science Foundation of Fujian Province of China (grants 2013J01147 and 2014J06019 to J.Z; grant 2014J01375 to M.X.; and grant 2016J01411 to H.Z.); and the National Key Research and Development Program of China (grant 2016YFC1305903). This work was also supported by the Program for New Century Excellent Talents in University (China) (NCET-13-0508 to J.Z.) and by grants from the NIH (R21 AG059217 to T.Y.H. and R21 AG048519, R01 AG021173, R01 AG038710, R01 AG044420, R01 NS046673, RF1 AG056130, and RF1 AG056114 to H.X.), as well as from the Tanz Family Fund (to H.X.) and the Cure Alzheimer's Fund (to H.X.). Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = jul,
day = "17",
doi = "10.1016/j.celrep.2018.06.055",
language = "English (US)",
volume = "24",
pages = "701--712",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}