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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01MH083680-06A1
Application #
8755977
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
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
Sun, Tao; Hevner, Robert F (2014) Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat Rev Neurosci 15:217-32
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; Hong, Janet; Li, Qingsong et al. (2013) MicroRNA cluster miR-17-92 regulates neural stem cell expansion and transition to intermediate progenitors in the developing mouse neocortex. Cell Rep 3:1398-406
Bian, Shan; Xu, Tian-le; Sun, Tao (2013) Tuning the cell fate of neurons and glia by microRNAs. Curr Opin Neurobiol 23:928-34
Sun, Tao; Ma, Quan-Hong (2013) Repairing neural injuries using human umbilical cord blood. Mol Neurobiol 47:938-45
Jung, Hea-Jin; Coffinier, Catherine; Choe, Youngshik et al. (2012) Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA. Proc Natl Acad Sci U S A 109:E423-31
Bian, Shan; Sun, Tao (2011) Functions of noncoding RNAs in neural development and neurological diseases. Mol Neurobiol 44:359-73
Otaegi, Gaizka; Pollock, Andrew; Hong, Janet et al. (2011) MicroRNA miR-9 modifies motor neuron columns by a tuning regulation of FoxP1 levels in developing spinal cords. J Neurosci 31:809-18

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