Graduate Thesis Or Dissertation

 

Characterization of the mechanism and function of C₂H₂ zinc finger protein CTIP2 in the developmental processes Público Deposited

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/9p290f70h

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  • CTIP2 is a C2H2 zinc finger transcription factor that plays important yet poorly understood roles in mouse development. CTIP2 is known to be highly expressed in the central nervous system, skin and T lymphocytes during embryogenesis. CTIP2-null mice die perinatally of unknown causes and exhibit defects in multiple organ systems including nervous and immune systems. The goals of our studies described herein were to characterize the mechanism of CTIP2-mediated transcriptional regulation and determine the role of CTIP2 during mouse development, focusing primarily on that of skin and the craniofacial complex. We analyzed the mechanisms of CTIP2-mediated repression in the neuronal context and uncovered that CTIP2 regulates transcription through recruitment of the nucleosome remodeling and deacetylation (NuRD) repressor complex to the target promoters. We also identified p57Kip2 as novel target gene of CTIP2 in neuroblastoma cells and showed that CTIP2 directly or indirectly binds to the promoter of p57Kip2 gene. We demonstrated for the first time that CTIP2 is highly expressed in the developing epidermis and in the underlying dermis. Analyses of the CTIP2-null mice revealed that CTIP2 controls both the terminal differentiation of keratinocytes and the establishment of the epidermal permeability barrier in a cell-autonomous manner. Our results also indicate that CTIP2 controls proliferation and early differentiation events of keratinocyte in a non-cell-autonomous manner by regulating the expression of growth factors, such as keratinocyte growth factor (KGF), that are expressed by the dermal fibroblast, and exert regulatory control over epidermal keratinocytes. CTIP2 is also highly expressed in the oral epithelium and the developing tooth. CTIP2 controls the terminal differentiation of ameloblasts, which are the enamel-producing cells of teeth, and in the absence of CTIP2 these cells do not differentiate, fail to polarize and do not express ameloblast-specific genes. Additionally, CTIP2 appears to be involved in the establishment of the asymmetry of the mouse incisors by inhibiting formation of the ameloblasts on the lingual aspect of the developing tooth.
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