Functional analysis of Tbx5 amd Tbx4 genes

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Wang, Song
Title Functional analysis of Tbx5 amd Tbx4 genes
Date 2004-08
Description Members of T-box family of transcription factors play critical roles in multiple aspects of development. Tbx5 and Tbx4 are a cognate gene pair arising from duplication of a common ancestral gene. Despite the high degree of sequence and structure similarity, these two genes show dramatic differences in their expression patterns and mutant phenotypes. To determine the extent of functional similarity and differences between these two closely related genes, the mouse Tbx5 gene was functionally replaced with Tbx4 sequence by gene targeting. Tbx4, when expressed in a Tbx5 specific pattern, partially restores expression of a Tbx5 downstream target ANF in the developing heart, but fails to rescue the posterior heart growth or cardiac looping defects of Tbx5 mutants. In cell culture, Tbx4 cannot cooperate with Nkx2.5 and fully activate ANF or cx40 expression to the same extent as Tbx5 did. Therefore, the functional differences of Tbx5 and Tbx4 in heart development stem from their different capabilities of cooperating with cofactors to regulate expression of downstream targets. Tbx4, when expressed in the forelimb region, replaces Tbx5 to initiate forelimb bud outgrowth and establishes the early AP and DV polarity of the forelimb bud. However, Tbx4 alone fails to support formation of the AER and continued outgrowth of the forelimb bud. Forelimb buds expressing both Tbx5 and Tbx4 exhibit no hindlimb features, suggesting Tbx4 is not sufficient to induce hindlimb features. This dissertation also studied the mechanism of arrested heart development in Tbx5 mutants. Hypoplasia in the posterior heart of Tbx5 mutants is a result of decreased cell proliferation followed by increased apoptosis in that region. Tbx5 regulates Raldh2 expression, and hence RA signaling, in the posterior heart. However, Raldh2 does not mediate all functions of Tbx5 in posterior heart development, other downstream effectors of Tbx5 are also required for the proper development of the posterior heart. The Nodal/Pitx2 pathway that establishes LR handedness of developing heart is not affected in Tbx5 mutants, suggesting the cardiac looping defect is a secondary defect due to the unbalanced growth of the heart tube..
Type Text
Publisher University of Utah
Subject Genetics ;Mice
Subject MESH Transcription, Genetic; Mutation
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Functional analysis of Tbx5 amd Tbx4 genes." Spencer S. Eccles Health Sciences Library. Print version of "Functional analysis of Tbx5 amd Tbx4 genes." available at J. Willard Marriott Library Special Collection. QH9.7 2004 .W35.
Rights Management © Song Wang.
Format Medium application/pdf
Format Extent 3,098,342 bytes
Identifier undthes,5388
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 3,098,375 bytes
ARK ark:/87278/s6tf0047
Setname ir_etd
Date Created 2012-04-24
Date Modified 2021-05-06
ID 191034
Reference URL https://collections.lib.utah.edu/ark:/87278/s6tf0047
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