Abnormal proliferation and differentiation of neural progenitors in the developing cerebral cortex can cause brain malformation and result in dysregulation of brain function such as epilepsy and mental retardation. Emerging evidence has shown that similar to protein coding genes, noncoding microRNAs (miRNAs) play critical roles in cortical development and are associated with the etiology of human neurological disorders. Our previous studies have demonstrated miRNA functions in cortical development by generating Dicer conditional knockout mice, in which miRNA biogenesis is specifically blocked in the embryonic cortex. We have identified potential miRNA target genes using proteomic approaches and RNA sequencing technique. We have also examined the role of specific miRNAs in cortical development. miRNAs are often located in the intronic regions of coding genes and transcribed together with host genes. However, the knowledge gap is how intronic miRNAs interact with target genes and host genes, and how expressions of miRNAs, target genes and host genes are precisely and properly regulated during cortical development. In this project, we will test a hypothesis that a regulatory loop of miRNAs, their target genes and host genes works cohesively to ensure proper development of neural progenitors in the developing cortex. Our preliminary study has identified a family of intronic miRNAs that is expressed in the developing mouse cortex. We have developed new tools to alter miRNA expression levels and to examine the specificity of miRNA silencing effects on target genes in vitro and in vivo during cortical development. Based on these findings, our proposed research focuses on three specific aims:
Aim 1 is to determine the role of this miRNA family in controlling neural progenitor proliferation and differentiation in vivo and in a culture system.
Aim 2 is to elucidate molecular mechanisms of the miRNA regulation by identifying specific target genes.
Aim 3 is to reveal the feedback regulation of the miRNA target gene on expression of this miRNA and its host gene in the process of controlling accurate numbers of cortical neural progenitors and proper neurogenesis. Our proposal will address a fundamental question of how a regulatory loop of miRNAs, their target genes and host genes controls proper cortical development. The success of our project should allow us to generate new tools to manipulate expressions of miRNAs and their target genes in vitro and in vivo. Because proper development of cortical neural progenitors is essential for normal brain function, our proposal should provide significant insights into developing a new diagnostic and therapeutic means using miRNAs for human brain malformations and neurological disorders.

Public Health Relevance

This project will investigate a regulatory loop of intronic miRNAs, their target genes and host genes in controlling proper development of the cerebral cortex. We will develop new methods to manipulate expressions of miRNAs and their target genes in vitro and in vivo. Our project should yield novel insights into the etiology of brain malformations and neurological disorders, which is mediated by a network of miRNAs- targets in the developing cortex.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Molecular Neurogenetics Study Section (MNG)
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Panchision, David M
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Weill Medical College of Cornell University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Gao, Yanxia; Sun, Tao (2016) Molecular regulation of hypothalamic development and physiological functions. Mol Neurobiol 53:4275-85
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
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
Zhang, Haijun; Kawase-Koga, Yoko; Sun, Tao (2015) Protein expression profiles characterize distinct features of mouse cerebral cortices at different developmental stages. PLoS One 10:e0125608
Sun, Tao; Hevner, Robert F (2014) Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat Rev Neurosci 15:217-32
Pollock, Andrew; Bian, Shan; Zhang, Chao et al. (2014) Growth of the developing cerebral cortex is controlled by microRNA-7 through the p53 pathway. Cell Rep 7:1184-96
Knauss, J L; Sun, T (2013) Regulatory mechanisms of long noncoding RNAs in vertebrate central nervous system development and function. Neuroscience 235:200-14
Li, Qingsong; Bian, Shan; Liu, Bingfang et al. (2013) Establishing brain functional laterality in adult mice through unilateral gene manipulation in the embryonic cortex. Cell Res 23:1147-9
Bian, Shan; Xu, Tian-le; Sun, Tao (2013) Tuning the cell fate of neurons and glia by microRNAs. Curr Opin Neurobiol 23:928-34

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