Genomic imprinting results in the preferential expression of the paternally, or maternally inherited allele of certain genes. Imprinted genes are highly expressed in the adult and developing brain, and this mode of epigenetic regulation of gene expression is essential for normal brain development and function. Moreover, defects in imprinted genes have been implicated in various mental illnesses including autism, psychosis, and mental retardation. We have recently developed a genome-wide sequencing strategy that led to the discovery of over 1300 new imprinted loci in the adult and developing brain and we have demonstrated that the repertoires of imprinted genes in the developing brain and adult male and female cortex are different. This suggests that genomic imprinting is a major and dynamic mode of epigenetic regulation, which has direct implications for the understanding of brain development and function, and of mental illnesses. The present proposal aims to unravel parental bias of gene expression in a genetically defined cortical cell population, the pan/albumin (PV) positive inhibitory interneurons that are thought to play major roles in the maturation of cortical circuits, and to be affected in various mental disorders. We will first optimize experimental strategies to purify PV cell-specific transcripts, and assess the nature of genes displaying parent of origin expression bias in mature PV interneurons. We will then compare the repertoire of imprinted genes in adult and developing PV cells, as well as in males and females. Finally we will investigate how the imprinted status of these gene is affected in mouse models of mental illness such as autism, schizophrenia and anxiety disorders. Our study will rely on the expertise and reagents from the Hensch group who has pioneered the study of PV-positive cortical interneurons function in the normal and pathological brain. In turn, our results will provide targets for further genetic, functional and circuit-wiring analysis by the Hensch and Lichtman's groups. The molecular and functional characterization of parental expression bias in PV cells will serve as a model for the experimental analysis of epigenetic controls of gene regulation in generically identified cortical cell types in the normal and pathological brain.

Public Health Relevance

Defects in genomic imprinting is associated with various mental illnesses such as autism, psychosis, and mental retardation. The molecular and functional characterization of genomic imprinting in genetically defined cortical populations is essential for a mechanistic understanding of normal cortical development and circuit formation, of the emergence of various mental illnesses, and for the improvement and invention of novel diagnostic and therapeutic tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH094271-04
Application #
8737970
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Mierau, Susanna B; Patrizi, Annarita; Hensch, Takao K et al. (2016) Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits. Biol Psychiatry 79:746-54
Morgan, Josh Lyskowski; Berger, Daniel Raimund; Wetzel, Arthur Willis et al. (2016) The Fuzzy Logic of Network Connectivity in Mouse Visual Thalamus. Cell 165:192-206
Perez, Julio D; Rubinstein, Nimrod D; Dulac, Catherine (2016) New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain. Annu Rev Neurosci 39:347-84
Kobayashi, Yohei; Ye, Zhanlei; Hensch, Takao K (2015) Clock genes control cortical critical period timing. Neuron 86:264-75
Perez, Julio D; Rubinstein, Nimrod D; Fernandez, Daniel E et al. (2015) Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain. Elife 4:e07860
Kaynig, Verena; Vazquez-Reina, Amelio; Knowles-Barley, Seymour et al. (2015) Large-scale automatic reconstruction of neuronal processes from electron microscopy images. Med Image Anal 22:77-88
Santoro, Stephen W; Dulac, Catherine (2015) Histone variants and cellular plasticity. Trends Genet 31:516-27
Sigal, Yaron M; Speer, Colenso M; Babcock, Hazen P et al. (2015) Mapping Synaptic Input Fields of Neurons with Super-Resolution Imaging. Cell 163:493-505
Morishita, Hirofumi; Cabungcal, Jan-Harry; Chen, Ying et al. (2015) Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons. Biol Psychiatry 78:396-402
Do, Kim Q; Cuenod, Michel; Hensch, Takao K (2015) Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia. Schizophr Bull 41:835-46

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