Myelinogenesis is a complex orchestration of multiple factors and cell types, including Oligodendrocytes (OLs), the myelinating cells of the CNS. The Fibroblast Growth Factor (FGF) family consists of 22 members subdivided into 7 sub-families. They act on a group of 4 Receptors (Rs), 3 of which are expressed in OLs. Our central model is that FGF signaling is an important regulator of numerous aspects of myelinogenesis, and that the developmentally-regulated, multiple responses of OLs to FGFs are due to a changing repertoire of specific FGF/FGF-R pairs, each of which contributes a subset of the overall phenotype at each stage of the lineage. Interruption of this carefully orchestrated pattern leads to myelin pathology with its attendant neurological risks. In this project period, we shall delve more deeply into the mechanisms by which this FGF system regulates specific steps in myelinogenesis and demyelinating disease.
Three Specific Aims are proposed.
In Aim I we study FGF-R signaling in OL development and myelin formation and maintenance. Using a series of cre/lox conditional knock-out mice with disruptions in specific FGF-R signaling, we investigate three key aspects of myelinogenesis, (1) postnatal OL differentiation and myelin assembly, (2) myelin maintenance during aging, and (3) OL progenitor generation during embryonic development.
In Aim II, we study FGF/FGF-R interactions in OL-lineage cells. Using FGFs that preferentially activate specific FGF-Rs and receptor-specific blocking antibodies, we test the hypothesis that during OL lineage progression, cells are differentially activated by particular FGFs, leading to selective activation of specific, developmentally expressed FGF-Rs, eliciting stage-specific cellular responses.
In Aim III, we study FGF-R function in demyelinating disease, building on the growing consensus that FGF signaling may play an important role in demyelinating disease. Using the cuprizone and lysolecithin models of de/remyelination applied to our Cre lox conditional FGF-R mutants (Aim I), we test the hypothesis that FGF- signaling in OLs, in a cell autonomous manner, is an important part of the molecular mechanism regulating the progression of demyelination, and the recovery with remyelination. The long term goal of this project is to understand the functional significance of the rigorously controlled developmental expression of FGF receptors both during OL differentiation leading to myelin biogenesis, as well as in myelin membrane function, maintenance and repair, and to apply this knowledge to an informed intervention in the treatment of demyelinating diseases such as multiple sclerosis. Project Narrative The long term goal of this project is to understand the functional significance of the rigorously controlled developmental expression of Fibroblast Growth Factor (FGF) receptors, both during oligodendocyte differentiation leading to myelin biogenesis, as well as in myelin membrane function, maintenance and repair, and to apply this knowledge to an informed intervention in the treatment of demyelinating diseases such as multiple sclerosis and other demyelinating diseases. Clarification of the role of FGF signaling in these processes can be expected to contribute to an informed clinical intervention to encourage remyelination and/or discourage demyelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038878-14
Application #
8288185
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
1999-07-05
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$317,275
Indirect Cost
$102,900
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Ishii, Akihiro; Furusho, Miki; Bansal, Rashmi (2013) Sustained activation of ERK1/2 MAPK in oligodendrocytes and schwann cells enhances myelin growth and stimulates oligodendrocyte progenitor expansion. J Neurosci 33:175-86
Verrier, Jonathan D; Jackson, Travis C; Gillespie, Delbert G et al. (2013) Role of CNPase in the oligodendrocytic extracellular 2',3'-cAMP-adenosine pathway. Glia 61:1595-606
Verrier, Jonathan D; Jackson, Travis C; Bansal, Rashmi et al. (2012) The brain in vivo expresses the 2',3'-cAMP-adenosine pathway. J Neurochem 122:115-25
Guardiola-Diaz, Hebe M; Ishii, Akihiro; Bansal, Rashmi (2012) Erk1/2 MAPK and mTOR signaling sequentially regulates progression through distinct stages of oligodendrocyte differentiation. Glia 60:476-86
Furusho, Miki; Kaga, Yoshimi; Ishii, Akihiro et al. (2011) Fibroblast growth factor signaling is required for the generation of oligodendrocyte progenitors from the embryonic forebrain. J Neurosci 31:5055-66
Dummula, Krishna; Vinukonda, Govindaiah; Chu, Philip et al. (2011) Bone morphogenetic protein inhibition promotes neurological recovery after intraventricular hemorrhage. J Neurosci 31:12068-82
Jackman, Nicole; Ishii, Akihiro; Bansal, Rashmi (2009) Oligodendrocyte development and myelin biogenesis: parsing out the roles of glycosphingolipids. Physiology (Bethesda) 24:290-7
Wang, S J; Furusho, M; D'Sa, C et al. (2009) Inactivation of fibroblast growth factor receptor signaling in myelinating glial cells results in significant loss of adult spiral ganglion neurons accompanied by age-related hearing impairment. J Neurosci Res 87:3428-37
Furusho, Miki; Dupree, Jeffrey L; Bryant, Melissa et al. (2009) Disruption of fibroblast growth factor receptor signaling in nonmyelinating Schwann cells causes sensory axonal neuropathy and impairment of thermal pain sensitivity. J Neurosci 29:1608-14
Bryant, M R; Marta, C B; Kim, F S et al. (2009) Phosphorylation and lipid raft association of fibroblast growth factor receptor-2 in oligodendrocytes. Glia 57:935-46

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