Dissection of Pitx2 gene function in secondary palate development : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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College Station, Tex. :
Texas A&M University System Health Science Center,
2009.
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| Subjects: |
| Abstract: | ABSTRACT: PITX2 was identified as the gene mutated in human Rieger syndrome, an autosomal dominant human disorder with multiple ocular and craniofacial clinic features. The murine homologue, Pitx2 encodes three isoforms (Pitx2a, Pitx2b and Pitx2c) that are co-expressed in oral ectoderm. Disruption of Pitx2 function leads to embryonic death in mice, and revealed multiple craniofacial defects (ocular, teeth and palate) that are in good agreement with the Rieger Syndrome individuals. Secondary palate formation is a complex process that involves several tightly coordinated steps: palate initiation, elevation and fusion. The mechanism that Pitx2[superscript null-/-] homozygous and Pitx2 hypomorph mutant embryos to dissect Ptix2[sic] function during the palatogenesis. We find Pitx2 controls secondary palate initiation by maintaining the maxillary expression of Fgf8 and its downstream target genes. PCNA and TUNEL assay on secondary palate shelves reveal cells proliferation and cell survival defects in Pitx2 mutant embryos. To investigate palate rugae Pitx2 function in later palatogenesis, we used timed-specific mutation and the results indicated Pitx2 function is necessary for normal later stage palatogenesis. Chimera mutant embryos suggest Pitx2 have autonomous function in palate rugae during the later palate development. We prove P-cadherin is the direct downstream target for Pitx2 in regulating normal palate rugae patterning. Pitx2 has a broadly expression during the whole embryogenesis procedure. The early embryonic lethality of the Ptix2[sic] null mice precludes analysis at later stages of embryonic development. To circumvent this problem and dissect Pitx2 function in molecular level, we generate a Pitx2 conditional allele with a dominant marker, an Flpe recombinase cassette. With the Flp reporter allele, this Pitx2flpLox allele becomes a dominant marker that can trace Pitx2 expression cells and daughters. This Pitx2flpLox mouse is a hypomorph with all three isoforms function being disturbed, while most part of the function can be rescued by removing the Neo cassette. This Pitx2flpLox allele will provide the first molecular insights into the functions of Pitx2 during the embryogenesis, which is critical to understandingt how loss of differenct dosage of Pitx2 functions in different embryo developmental stages leads to human disease in multiple organs. |
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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 for the degree of Doctor of Philosophy May 2009." Approved as to style and content by: James F. Martin, Mingyao Liu, Richard Behringer, Pierre McCrea. |
| Physical Description: | xiv, 128 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 120-127). |