Dissertation/Thesis Abstract

Human myelin proteolipid protein gene expression in brain is governed by intronic regulatory elements
by Hamdan, Hamdan, Ph.D., University of Arkansas for Medical Sciences, 2012, 141; 3551926
Abstract (Summary)

The PLP1 gene is highly expressed in oligodendrocytes, encoding the most abundant protein in myelin from the central nervous system (CNS). Expression of the gene is tightly regulated during CNS development, with abnormal levels being implicated in some forms of X-linked dysmyelinating leukodystrophies (Pelizaeus-Merzbacher disease and spastic paraplegia type 2) in males with atypical PLP1 gene dosage. Thus, it is important to understand how this gene is regulated not only for insight into associated genetic disorders, but also to aid in the promotion of remyelination in patients suffering from demyelinating diseases such as multiple sclerosis (MS). However, not much is known about the mechanisms that control human PLP1 gene expression. Previous studies from our laboratory have demonstrated that the first intron of the mouse PLP1 gene is required to attain high levels of reporter gene (lacZ) expression in brain directed by the PLP1 promoter. Yet the identity of these regulatory element(s) within intron 1 remains unknown, although it has be postulated that it may lay within a 1.2 kb region designated as the wmN1 enhancer because this region augmented expression of a minimally promoted reporter gene ( lacZ) in white matter areas of brain.

To test whether the first intron of the human PLP1 gene likewise contains positive regulatory elements that are important for its expression, PLP1-lacZ fusion genes were generated which include various portions of PLP1 intron 1 DNA. The relative levels of expression for these constructs were evaluated by transfection analysis in an oligodendroglial cell line (Oli-neu), and in transgenic mice. Results presented in this dissertation indicate that PLP1 intron 1 is required for maximal levels of expression in both Oli-neu cells and transgenic mice. Multiple elements, besides wmN1, appear to govern this response in Oli-neu cells, while the wmN1 region is primarily responsible in transgenic mice. This study demonstrates for the first time that the wmN1 enhancer can work in collaboration with its native promoter to augment PLP1 gene expression. Understanding how the gene is regulated in man during normal development and during remyelination is necessary as a step towards devising therapies that restore function in patients suffering from MS, and may provide insight to the etiology surrounding some cases of dysmyelinating disorders linked to PLP1.

Indexing (document details)
Advisor: Wight, Patricia A.
Commitee: Barger, Steven, Hayar, Abdallah, McGehee, Robert, Simmen, Frank, Ware, Jerry
School: University of Arkansas for Medical Sciences
Department: Physiology and Biophysics
School Location: United States -- Arkansas
Source: DAI-B 74/06(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Neurosciences, Genetics
Keywords: Brain, Gene expression in brain, Myelin, Oligodendrocytes, PLP1 gene, Proteolipid proteins
Publication Number: 3551926
ISBN: 9781267900791
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