MicroRNAs : novel regulators in neural stem cell development and teratology : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2009]
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| Subjects: |
| Abstract: | ABSTRACT: The dorsal neuroepithelium is the principle developmental origin of the projection neurons of the cortical plate, while the ventral neuroepithelium is the site of origin of inter-neurons that populate the cortical plate. The mechanism by which cells born in the ventricular zone migrate out to populate the cortex in "inside out" pattern is a highly regulated event. However, the mechanism by which these the timed events takes place is less understood. Micro-RNAs (miRNAs) are a class of small non-coding RNAs that regulate cell fate by rapidly destabilizing gene networks. We hypothesized that miRNAs could mediate ethanol's teratogenic effects, and examined the ethanol-sensitivity of miRNAs in an embryonic mouse cerebral cortex-derived neurosphere culture model. Ethanol, at a level attained in alcoholics, significantly suppressed the expression of four miRNAs, miR-21, 335, 9, and 153, whereas a lower ethanol concentration, attainable during social drinking, induced miR-335 expression. Antisense-mediated suppression of miR-21 expression resulted in apoptosis, suggesting that miR-21 is an anti-apoptotic factor. MiR-335 knockdown promoted cell proliferation, and prevented death induced by concurrently suppressing miR-21; indicating that miR-335 is a pro-apoptotic, antimitogenic factor, whose actions are antagonistic to miR-21. In Chapter III, we show that miR335 acts as a molecular brake, to prevent fetal neuroepithelial cell maturation. FGF2 induced miR335 expression, and conversely, in the presence of FGF, miR335 suppression de-repressed 116 maturation-associated genes. These data suggesting that miR335 represses maturation without influencing stem cell renewal. MiR335 expression localizes to nestin-positive neuroepithelial cells in the basal ventricular zone (VZ) during the peak period of fetal neurogenesis, and its expression is turned off in the apical mitotic zone of the VZ, and in the subventricular zone (SVZ). MiR335's disappearance is accompanied by the appearance of maturation-associated factors like PDGFr[alpha] and NG2 in apical VZ and SVZ. Moreover, in the presence of extracellular matrix, MiR335-depleted neural progenitors express PDGFr[alpha] and exhibit morphological transformation into oligodendrocyte progenitor-like cells. Collectively, the suppression of microRNAs is consistent with ethanol induction of cell cycle and neuroepithelial maturation, in the absence of apoptosis. These data advance a mechanism whereby teratogens can shape complex, divergent developmental processes. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment for the requirements of the degree of Doctor of Philosophy May 2009." Approved as to style and content by: Rajesh C. Miranda, Farida Sohrabji, C. Jane Welsh, Gerald D. Frye, William H. Griffith. |
| Physical Description: | xi, 140 leaves : illustrations (some color) ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 138-139). |