Increasing evidence indicates that insulin-like growth factor-I (IGF-I) plays an important role in the development of neural cells in the central nervous system, including oligodendrocyte lineage cells and myelination, as well as promoting regeneration of oligodendrocyte lineage cells following injury. We hypothesize that IGF-I acts directly on the cells of oligodendrocyte lineage by mechanisms that are initiated by interaction with its cell surface receptor, the type 1 IGF receptor (IGF1R), and in turn by regulation of gene expression. Our hypothesis is supported by our data and those of others showing that: 1) IGF-I promotes proliferation and differentiation of oligodendrocyte lineage cells in culture; 2) overexpression of IGF-I in transgenic (Tg) mice during postnatal development increases the number of oligodendrocyte lineage cells; 3) in animals subjected to demyelinating insults, the expression of IGF-I and IGF1R genes is induced in a fashion temporally and spatially related to the injury; 4) IGF-I protects myelination from a variety of CNS injury; and 5) blunting IGFIR expression specifically in oligodendrocytes results in brain retardation and hypomyelination in the mutant mice. Furthermore, our recent studies show that IGF-I regulates multiple gene expression and modification of histone proteins in cells of oligodendrocyte line. In this application, we propose two specific aims to further examine our hypotheses: 1) To determine IGF actions on the development of oligodendrocyte precursors in vivo, we will examine oligodendrocyte precursors in newly developed Tg mice that overexpress IGF-I during embryonic and early postnatal development, and in mutant mice in which IGF1R expression is specifically blunted in oligodendrocyte precursors. 2) To delineate IGF-I signaling mechanisms leading to the gene regulation that promotes oligodendrocyte development, we will determine a) IGF-I in vivo regulation of global gene expression in oligodendrocytes and their precursors using laser captured microdissection and DNA array; and b) IGF-I actions on chromatin remodeling. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS048868-01
Application #
6804321
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (05))
Program Officer
Utz, Ursula
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$343,707
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Yan, Yun; Li, Xiaoyu; Kover, Karen et al. (2013) CREB participates in the IGF-I-stimulation cyclin D1 transcription. Dev Neurobiol 73:559-70
O'Kusky, John; Ye, Ping (2012) Neurodevelopmental effects of insulin-like growth factor signaling. Front Neuroendocrinol 33:230-51
Liu, Wen; D'Ercole, Joseph A; Ye, Ping (2011) Blunting type 1 insulin-like growth factor receptor expression exacerbates neuronal apoptosis following hypoxic/ischemic injury. BMC Neurosci 12:64
Lehtinen, Maria K; Zappaterra, Mauro W; Chen, Xi et al. (2011) The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69:893-905
Ye, Ping; Hu, Qichen; Liu, Hedi et al. (2010) beta-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial cultures. Glia 58:1031-41
Liu, Hedi; Hu, Qichen; D'ercole, A Joseph et al. (2009) Histone deacetylase 11 regulates oligodendrocyte-specific gene expression and cell development in OL-1 oligodendroglia cells. Glia 57:1-12
Joseph D'Ercole, A; Ye, Ping (2008) Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149:5958-62
Liu, Hedi; Hu, Qichen; Kaufman, Amanda et al. (2008) Developmental expression of histone deacetylase 11 in the murine brain. J Neurosci Res 86:537-43
Lagarde, William H; Benjamin, Robert; Heerens, Ann T et al. (2007) A non-transformed oligodendrocyte precursor cell line, OL-1, facilitates studies of insulin-like growth factor-I signaling during oligodendrocyte development. Int J Dev Neurosci 25:95-105
Ye, Ping; Kollias, George; D'Ercole, A Joseph (2007) Insulin-like growth factor-I ameliorates demyelination induced by tumor necrosis factor-alpha in transgenic mice. J Neurosci Res 85:712-22

Showing the most recent 10 out of 13 publications