A critical question in biology is how stem and progenitor cells integrate multiple signals from their environment to make decisions to proliferate or to exit the cell cycle and differentiate. The oligodendrocyte lineage has been the focus of numerous studies on how specific growth factors including platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2) and insulin-like growth factor-I (IGF-I) regulate the generation of oligodendrocytes. Our previous studies demonstrated that 1) IGF-I is required for maximal stimulation of oligodendrocyte progenitor cells (OPCs) by PDGF and FGF-2, 2) IGF-I and FGF-2 are synergistic in promoting DNA synthesis in OPCs, and 3) IGF-I, in the presence of FGF-2, increases recruitment of OPCs into the cell cycle. The immediate goals of this proposal are to test the hypotheses that 1) IGF-I, FGF-2 and PDGF coordinately regulate cell cycle progression in OPCs by inducing specific molecular components of the cell cycle, and 2) IGF actions through the IGF type I receptor (IGF-IR) are essential for maximal OPC proliferation. To test the first hypothesis, experiments are proposed to determine how PDGF, FGF-2 and IGF-I coordinate to amplify the induction and activation of the cyclin-cyclin-dependent protein kinases that are essential for G1, S and G2 progression in the OPC. To test the second hypothesis, we will investigate the function of endogenous signaling through the IGF-IR in OPCs in vitro and in vivo using ribozyme technologies and transgenic approaches to inhibit IGF-IR expression and activation. The data from these studies will be important to our understanding of cell cycle regulation in the OPC and will be of broader interest to the field of signal integration in progenitor cell proliferation during development. Moreover, the investigations proposed here will provide the basis for understanding the mechanisms by which proliferation of adult oligodendrocyte progenitors could be enhanced to promote repair of demyelinating lesions in central nervous system disorders such as Multiple Sclerosis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS037560-08
Application #
7022202
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Utz, Ursula
Project Start
1998-12-20
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2008-02-28
Support Year
8
Fiscal Year
2006
Total Cost
$332,381
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Neurosciences
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Min, Jungsoo; Singh, Sukhwinder; Fitzgerald-Bocarsly, Patricia et al. (2012) Insulin-like growth factor I regulates G2/M progression through mammalian target of rapamycin signaling in oligodendrocyte progenitors. Glia 60:1684-95
Tyler, William A; Jain, Mohit Raja; Cifelli, Stacey E et al. (2011) Proteomic identification of novel targets regulated by the mammalian target of rapamycin pathway during oligodendrocyte differentiation. Glia 59:1754-69
Tyler, William A; Gangoli, Nitish; Gokina, Pradeepa et al. (2009) Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. J Neurosci 29:6367-78
Romanelli, Robert J; Wood, Teresa L (2008) Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses. J Neurochem 105:2055-68
Wood, Teresa L; Loladze, Vaho; Altieri, Stefanie et al. (2007) Delayed IGF-1 administration rescues oligodendrocyte progenitors from glutamate-induced cell death and hypoxic-ischemic brain damage. Dev Neurosci 29:302-10
Romanelli, Robert J; LeBeau, Andrew P; Fulmer, Clifton G et al. (2007) Insulin-like growth factor type-I receptor internalization and recycling mediate the sustained phosphorylation of Akt. J Biol Chem 282:22513-24
Frederick, Terra J; Min, Jungsoo; Altieri, Stefanie C et al. (2007) Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathways. Glia 55:1011-22
Ness, Jennifer K; Scaduto Jr, Russell C; Wood, Teresa L (2004) IGF-I prevents glutamate-mediated bax translocation and cytochrome C release in O4+ oligodendrocyte progenitors. Glia 46:183-94
Frederick, Terra J; Wood, Teresa L (2004) IGF-I and FGF-2 coordinately enhance cyclin D1 and cyclin E-cdk2 association and activity to promote G1 progression in oligodendrocyte progenitor cells. Mol Cell Neurosci 25:480-92
Ness, Jennifer K; Wood, Teresa L (2002) Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis. Mol Cell Neurosci 20:476-88

Showing the most recent 10 out of 14 publications