Myelination is essential for brain development and function but the precise mechanisms that control the development of myelinating oligodendrocytes are not known. In demyelinating diseases such as multiple sclerosis, the loss of myelin is also thought to contribute to neurodegeneration. Myelin abnormalities of unknown origin are also found in autism, schizophrenia, and Alzheimer's disease. Candidates to regulate myelination include extrinsic factors such as extracellular matrix (ECM) molecules found in the developing brain. In contrast to neurons, little is known about the oligodendrocyte receptors and signaling mechanisms that regulate interactions with ECM. The long term goal of our research is to understand to what degree ECM regulates myelination and to determine how ECM signals lead to phenotypic changes in myelinating cells. In the current proposal we will test the hypothesis that the ECM molecule laminin enhances the survival and differentiation of oligodendrocytes by acting through specific transmembrane receptors and signaling effector molecules. We will first determine the oligodendrocyte receptor requirements for laminins using several approaches to disrupt or addback individual receptor interactions in oligodendrocytes alone or in coculture with neurons. Fyn kinase is required for laminin to enhance oligodendrocyte survival and differentiation, but the molecular mechanisms underlying this requirement are not known. We will test the hypothesis that laminins modulate Fyn regulatory mechanisms using experiments designed to disrupt Fyn regulatory molecules as well as to monitor Fyn regulatory mechanisms that are activated by laminins. Finally, we will test whether Fyn regulatory mechanisms are modulated by laminins in vivo using a model for laminin deficiency that causes CNS dysmyelination. These studies are designed to uncover key mechanisms in the reciprocal axonal-glial signaling events that trigger and regulate the processes of oligodendrocyte survival, differentiation, and myelination. We hope to discover signals that stimulate myelination, a process where specialized brain cells produce an insulation, termed myelin, that is necessary for the survival and function of neurons. In doing so, we may learn which of these signals are missing or scrambled in diseases such as Multiple Sclerosis where myelin is destroyed, and, may learn how to protect neurons in neurodegenerative diseases such as Alzheimer's. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS054042-01A1
Application #
7148440
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Utz, Ursula
Project Start
2006-08-02
Project End
2011-01-31
Budget Start
2006-08-02
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$191,849
Indirect Cost
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Leiton, Cindy V; Aranmolate, Azeez; Eyermann, Christopher et al. (2015) Laminin promotes metalloproteinase-mediated dystroglycan processing to regulate oligodendrocyte progenitor cell proliferation. J Neurochem 135:522-38
Menezes, Michael J; McClenahan, Freyja K; Leiton, Cindy V et al. (2014) The extracellular matrix protein laminin ?2 regulates the maturation and function of the blood-brain barrier. J Neurosci 34:15260-80
Relucio, Jenne; Menezes, Michael J; Miyagoe-Suzuki, Yuko et al. (2012) Laminin regulates postnatal oligodendrocyte production by promoting oligodendrocyte progenitor survival in the subventricular zone. Glia 60:1451-67
Eyermann, Christopher; Czaplinski, Kevin; Colognato, Holly (2012) Dystroglycan promotes filopodial formation and process branching in differentiating oligodendroglia. J Neurochem 120:928-47
Colognato, Holly; Tzvetanova, Iva D (2011) Glia unglued: how signals from the extracellular matrix regulate the development of myelinating glia. Dev Neurobiol 71:924-55
Galvin, Jason; Eyermann, Christopher; Colognato, Holly (2010) Dystroglycan modulates the ability of insulin-like growth factor-1 to promote oligodendrocyte differentiation. J Neurosci Res 88:3295-307
Kuo, Emory; Park, Daniel K; Tzvetanova, Iva D et al. (2010) Tyrosine phosphatases Shp1 and Shp2 have unique and opposing roles in oligodendrocyte development. J Neurochem 113:200-12
Barros, Claudia S; Nguyen, Tom; Spencer, Kathryn S R et al. (2009) Beta1 integrins are required for normal CNS myelination and promote AKT-dependent myelin outgrowth. Development 136:2717-24
Relucio, Jenne; Tzvetanova, Iva D; Ao, Wei et al. (2009) Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development. J Neurosci 29:11794-806