Characterization of Chd7 in central nervous system neural stem cells

Summary

Principal Investigator: JOSEPH ANTHONY MICUCCI
Abstract: DESCRIPTION (provided by applicant): Tightly regulated gene expression is essential for the proper function of neural stem cells in developing and adult tissues. Modulation of chromatin states through epigenetic modifications is proposed to regulate neurogenesis in the subventricular zone (SVZ) of the lateral ventricle, but the precise mechanisms involved are not defined. The SVZ neural stem cell niche is responsible for producing olfactory bulb (OB) interneurons that play an integral role in olfactory memory and olfactory signal transduction. While histone modifying genes such as the Trithorax-group member Mll1 and the Polycomb-group member Bmi1 have been identified as potent regulators of SVZ neural stem cells, the contribution of chromatin remodeling in neural stem cell regulation has not been established. Previous studies in our laboratory have demonstrated that the ATP- dependent chromatin remodeling enzyme CHD7 is essential for proper neural stem cell function and neurogenesis in the olfactory sensory epithelium and inner ear. In humans, mutations in CHD7 cause CHARGE Syndrome, a multiple congenital anomaly disorder that affects development of the eyes, ears, nose, and central nervous system (CNS). CHD7 has also been linked to developmental disorders including autism spectrum disorder and Kallmann Syndrome, which is characterized by hypogondotropic hypogonadism. Chd7 is emerging as a global regulator of neurogenesis in both the subventricular zone and in sensory epithelia. A more thorough understanding of genetic targets for Chd7 in the SVZ may uncover novel mechanisms regulating neurogenesis, and help explain the etiologies of sensory and central nervous system defects observed in CHARGE Syndrome and related disorders. My global hypothesis is that CHD7 regulates proliferation, maintenance and neurogenesis of perinatal and adult central nervous system neural stem cells. To test this hypothesis, I propose the following specific aims: Aim 1: Determine the in vivo Chd7 regulation of subventricular zone proliferation and neurogenesis of olfactory bulb interneurons. Aim 2: Define the in vitro role of Chd7 in the self-renewal and cell fate specification of subventricular zone neural stem cells. Aim 3: Elucidate CHD7 binding to enhancer elements of genes involved in neuronal differentiation and cell cycle maintenance in the subventricular zone.
Funding Period: 2012-12-04 - 2013-10-31
more information: NIH RePORT

Top Publications

  1. pmc CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome
    Joseph A Micucci
    Department of Biological Chemistry
    Hum Mol Genet 23:434-48. 2014

Research Grants

  1. Developmental Mechanisms of the Chromodomain Gene Chd7
    Donna M Martin; Fiscal Year: 2013
  2. Identification and regulation of quiescent stemcells in the adult brain
    ANGEL RICARDO MALDONADO; Fiscal Year: 2013
  3. Specification of Peripheral Olfactory Stem Cells
    Anthony S LaMantia; Fiscal Year: 2013
  4. Translational Regulation of Adult Neural Stem Cells
    Xinyu Zhao; Fiscal Year: 2013
  5. Induced Pluripotent Stem Cells for Modeling Congenital Deafness
    Eri Hashino; Fiscal Year: 2013
  6. Developmental Origins of the Germinal Niche
    Arturo Alvarez-Buylla; Fiscal Year: 2013
  7. Role of Ascl1 in glioma
    Tou Yia Vue; Fiscal Year: 2013
  8. Epigenomic Modifications in Mammalian Neurogenesis
    Gerd P Pfeifer; Fiscal Year: 2013
  9. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
  10. PROGRAMS OF GENE EXPRESSION IN OLFACTORY NEUROGENESIS
    JOHN J NGAI; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome
    Joseph A Micucci
    Department of Biological Chemistry
    Hum Mol Genet 23:434-48. 2014
    ..Our findings demonstrate critical, cooperative roles for RA and CHD7 in SVZ neural stem cell function and inner ear development, suggesting that altered RA signaling may be an effective method for treating Chd7 deficiency...

Research Grants30

  1. Developmental Mechanisms of the Chromodomain Gene Chd7
    Donna M Martin; Fiscal Year: 2013
    ..Improved understanding of tissue-specific requirements for Chd7 might also improve the diagnosis and treatment of CHARGE-related inner ear and other developmental defects. ..
  2. Identification and regulation of quiescent stemcells in the adult brain
    ANGEL RICARDO MALDONADO; Fiscal Year: 2013
    ..Together these studies will provide information on the identity and regulation of these quiescent neural stem cells. ..
  3. Specification of Peripheral Olfactory Stem Cells
    Anthony S LaMantia; Fiscal Year: 2013
    ..abstract_text> ..
  4. Translational Regulation of Adult Neural Stem Cells
    Xinyu Zhao; Fiscal Year: 2013
    ..These data will provide critical information regarding not only the function of FMRP in neurogenesis but also the function of stage-specific neurogenesis in learning and memory. ..
  5. Induced Pluripotent Stem Cells for Modeling Congenital Deafness
    Eri Hashino; Fiscal Year: 2013
    ..The proposed study will provide valuable information on the prenatal diagnosis and targeted treatment of this devastating congenital disorder. ..
  6. Developmental Origins of the Germinal Niche
    Arturo Alvarez-Buylla; Fiscal Year: 2013
    ..These findings could help understand the mechanism of hydrocephalus, a condition that afflicts 1 in 300 infants, and help develop new strategies for the use of postnatal neural stem cells for brain repair...
  7. Role of Ascl1 in glioma
    Tou Yia Vue; Fiscal Year: 2013
    ..The culmination of this study will provide new insights into the heterogeneity and molecular mechanisms of glioma tumors. ..
  8. Epigenomic Modifications in Mammalian Neurogenesis
    Gerd P Pfeifer; Fiscal Year: 2013
    ....
  9. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  10. PROGRAMS OF GENE EXPRESSION IN OLFACTORY NEUROGENESIS
    JOHN J NGAI; Fiscal Year: 2013
    ....
  11. CHEMOKINE RECEPTOR FUNCTION IN THE NERVOUS SYSTEM
    Richard J Miller; Fiscal Year: 2013
    ....
  12. Stem Cells for Brain Repair
    DANIEL ALAN PETERSON; Fiscal Year: 2013
    ..This study will include both young and aged animals to address this important, clinically relevant factor. ..
  13. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  14. Elucidating the Numb Signaling Pathway
    Weimin Zhong; Fiscal Year: 2013
    ..A better understanding of how stem cells are regulated will provide novel insights for their therapeutic use to repair tissues damaged by disease, injury or aging. ..
  15. Quantifying Changes in Neural Stem Cell Lineages in the Aging Niche
    Sally Temple; Fiscal Year: 2013
    ....
  16. The Lis1-Nde1 pathway in cerebral cortical development
    Yuanyi Feng; Fiscal Year: 2013
    ..The proposal outlines combined mouse genetic and cell biological experiments to study the function of LIS1 and its associated Nde1 genes in regulating the self- renewal and neurogenesis during cerebral cortical development. ..
  17. GENETIC DETERMINANTS OF LOCAL CIRCUIT ORGANIZATION
    Charles A Greer; Fiscal Year: 2013
    ..abstract_text> ..
  18. ALTERATIONS IN ADULT NEUROGENESIS DURING WEST NILE VIRUS ENCEPHALITIS
    MICHAEL JOHN VASEK; Fiscal Year: 2013
    ..Furthermore, knowledge about the behavior of neural stem cells within inflamed conditions may help guide the development of stem cell-based therapeutics for other CNS diseases with inflammation. ..
  19. CHARACTERIZATION OF NEURAL STEM CELLS IN THE ADULT BRAIN
    Arturo Alvarez-Buylla; Fiscal Year: 2013
    ..This work will help in the development of novel strategies for brain repair and suggest how derailed proliferation of endogenous precursors might lead to tumor formation. ..