The proper development and function of the human cerebral cortex is controlled by precise regulation of gene expression. Many human neurological disorders, such as epilepsy, schizophrenia and autism, are associated with abnormal structural formation and connection in the cortex. The etiology of these neurological disorders is poorly understood. Recently, a post-transcriptional gene regulation machinery has been identified with the discovery of a class of ~22 nucleotide, endogenous, noncoding, small RNAs, called microRNAs (miRNAs). The mature miRNA controls gene expression by binding to the 3'-untranslated region (3'-UTR) of its target gene and silencing protein translation. Many miRNAs are expressed in the developing brain, but little is known about whether and how miRNAs control development of the cerebral cortex. In this project we will test the hypothesis that noncoding miRNAs maintain the neural progenitor pool and control neuronal production during cortical development. Our hypothesis makes three testable predictions that we will address using neurogenetic and proteomic approaches in the following three Specific Aims.
Aim 1 is to test the prediction that microRNA function is required for cortical development. We have created mouse models in which miRNA biogenesis is temporally and spatially blocked in the cortex. We found that the miRNA deficient mouse has smaller cortex. We will determine miRNA function in development of neural progenitors and postmitotic neurons, in cortical neuronal production and anterior and posterior pattern formation.
Aim 2 is to examine the distinct role of two specific miRNAs in controlling cortical neuronal production. Using microarrays we identified two miRNAs with temporally differential expression levels during cortical development. We will examine their role in neuronal production by altering their cortical expression levels.
Aim 3 is to reveal the mechanisms of miRNA function by identifying their target proteins. We will examine the silencing effect of two specific miRNAs on potential target proteins during cortical development. We will identify new miRNA targets by creating protein expression profiles of miRNA deficient and control cortices using proteomic approaches. The discovery of noncoding microRNAs has revealed a novel machinery of gene regulation. Our project should provide important insights into post-transcriptional gene regulation, which is controlled by miRNAs, in normal brain formation and function. Our results will expand our ability uncover the miRNA-mediated mechanisms that cause mental illness and behavioral abnormalities in humans.

Public Health Relevance

This project will investigate the function and molecular mechanisms of noncoding microRNA-mediated post-transcriptional gene regulation during cortical development. The success of our project should yield significant insights into the etiology of human mental disorders, which can be caused by mutations of not only coding genes but also noncoding molecules such as microRNAs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083680-04
Application #
8220993
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2009-04-23
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$418,275
Indirect Cost
$170,775
Name
Weill Medical College of Cornell University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Miao, Nan; Bian, Shan; Lee, Trevor et al. (2018) Opposite Roles of Wnt7a and Sfrp1 in Modulating Proper Development of Neural Progenitors in the Mouse Cerebral Cortex. Front Mol Neurosci 11:247
Zhang, Haijun; Zhang, Longbin; Sun, Tao (2018) Cohesive Regulation of Neural Progenitor Development by microRNA miR-26, Its Host Gene Ctdsp and Target Gene Emx2 in the Mouse Embryonic Cerebral Cortex. Front Mol Neurosci 11:44
Miao, Nan; Jin, Junghee; Kim, Seung-Nam et al. (2018) Hippocampal MicroRNAs Respond to Administration of Antidepressant Fluoxetine in Adult Mice. Int J Mol Sci 19:
Zeng, Zhiwei; Miao, Nan; Sun, Tao (2018) Revealing cellular and molecular complexity of the central nervous system using single cell sequencing. Stem Cell Res Ther 9:234
Floris, Gabriele; Zhang, Longbin; Follesa, Paolo et al. (2017) Regulatory Role of Circular RNAs and Neurological Disorders. Mol Neurobiol 54:5156-5165
Jin, Junghee; Kim, Seung-Nam; Liu, Xuqing et al. (2016) miR-17-92 Cluster Regulates Adult Hippocampal Neurogenesis, Anxiety, and Depression. Cell Rep 16:1653-1663
Gao, Yanxia; Sun, Tao (2016) Molecular regulation of hypothalamic development and physiological functions. Mol Neurobiol 53:4275-85
Zhang, Haijun; Lamon, Brian D; Moran, George et al. (2016) Pitavastatin Differentially Modulates MicroRNA-Associated Cholesterol Transport Proteins in Macrophages. PLoS One 11:e0159130
Abdullah, Aisha I; Zhang, Haijun; Nie, Yanzhen et al. (2016) CDK7 and miR-210 Co-regulate Cell-Cycle Progression of Neural Progenitors in the Developing Neocortex. Stem Cell Reports 7:69-79
Liu, Xuqing; Sun, Tao (2016) microRNAs and Molecular Pathogenesis of Microcephaly. Curr Mol Pharmacol 9:300-304

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