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Functionally distinct roles for T and Tbx6 during mouse development
The mouse T-box transcription factors T and Tbx6 are co-expressed in the primitive streak and have unique domains of expression; T is expressed in the notochord, while Tbx6 is expressed in the presomitic mesoderm. T-box factors are related through a shared DNA binding domain, the T-domain, and can t...
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Published in: | Biology open 2020-08, Vol.9 (8) |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The mouse T-box transcription factors T and Tbx6 are co-expressed in the primitive streak and have unique domains of expression; T is expressed in the notochord, while Tbx6 is expressed in the presomitic mesoderm. T-box factors are related through a shared DNA binding domain, the T-domain, and can therefore bind to similar DNA sequences at least
We investigated the functional similarities and differences of T and Tbx6 DNA binding and transcriptional activity
and their interaction genetically
We show that at one target,
, the T-domains of T and Tbx6 have different affinities for the binding sites present in the mesoderm enhancer. We further show using
assays that T and Tbx6 differentially affect transcription with Tbx6 activating expression tenfold higher than T, that T and Tbx6 can compete at target gene enhancers, and that this competition requires a functional DNA binding domain. Next, we addressed whether T and Tbx6 can compete
First, we generated embryos that express Tbx6 at greater than wild-type levels embryos and show that these embryos have short tails, resembling the
heterozygous phenotype. Next, using the dominant-negative
allele, we show that
embryos share similarities with embryos homozygous for the
hypomorphic allele
, specifically fusions of several ribs and malformation of some vertebrae. Finally, we tested whether Tbx6 can functionally replace T using a knockin approach, which resulted in severe
null-like phenotypes in chimeric embryos generated with ES cells heterozygous for a
knockin at the
locus. Altogether, our results of differences in affinity for DNA binding sites and transcriptional activity for T and Tbx6 provide a potential mechanism for the failure of Tbx6 to functionally replace T and possible competition phenotypes
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ISSN: | 2046-6390 2046-6390 |
DOI: | 10.1242/BIO.054692 |