A new mouse model with a myelinating disorder has been generated. It is severely hypomyelinated between birth and P50, and exhibits severe tremors during this period. After P50, myelin begins to accumulate in the brain, but it never completely achieves control levels. Hypomyelination occurs over the 'critical"""""""" period of brain development when axonal sprouting, neural networks, synaptic connections, and neuronal-glial relationships are being established. The overall objective of this proposal is to use this mouse as a unique model to study the cellular basis for the """"""""delayed"""""""" myelination, to determine how the brain can """"""""recover"""""""" from a major hypomyelinating event, to determine the cellular and functional consequences of retarded myelination during development and to determine how transient hypomyelination during a critical period of brain development influences the survival and structural integrity of neurons und neuronal connectivity in the brain. This application consists of three specific aims: (1) Examine myelination in the brains of the JOE (i.e. J37 Over-Expressing) mice. In this aim myelination will be examined in JOE and WT mice using an array of morphological and biochemical approaches; (2) determine the cellular mechanisms responsible for the delay in myelination in the JOE mice; (3) define the nature and extent of axon pathology, neuronal degeneration and neuronal abnormalities in the JOE mice. The proposed experiments will determine if the retarded myelination in JOE mice is normal or abnormal and if the mice form structurally normal myelin. The studies will assess the effect of golli J37 overexpression on oligodendrocyte (OL) development, survival and maturation; whether golli overexpression occurs in OL precursors, late progenitors, or immature OLs; how this affects the survival, differentiation or migration of these cells in JOE mice; and which cells are responsible for the later myelination in JOE mice. The effects of hypomyelination during the """"""""critical"""""""" period of brain development on several aspects of neuronal biology will be determined. These include: (a) cerebellar and cerebral cortical organization; (b) susceptibility to hypomyelination and survival; (c) axonal integrity and (d) axonal and dendritic organization. These studies are relevant to demyelinating diseases, like MS and leukodystrophies, and will enhance our understanding of myelination, remyelination and the effects of hypomyelination on neural function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-G (02))
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Utz, Ursula
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Fulton, Daniel; Paez, Pablo; Spreur, Vilma et al. (2011) Developmental activation of the proteolipid protein promoter transgene in neuronal and oligodendroglial cells of neostriatum in mice. Dev Neurosci 33:170-84
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