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Dev Biol. 2014 Aug 15;392(2):483-93. doi: 10.1016/j.ydbio.2014.05.010. Epub 2014 May 20.

A distant downstream enhancer directs essential expression of Tbx18 in urogenital tissues.

Author information

1
Department of Cell & Developmental Biology, University of Illinois, Urbana, IL, USA; Institute for Genomic Biology, University of Illinois, Urbana, IL, USA.
2
St. Vincent׳s Institute, Melbourne, Australia.
3
Institute for Genomic Biology, University of Illinois, Urbana, IL, USA.
4
Roy J. Carver Biotechnology Center, University of Illinois, Urbana, IL, USA.
5
Institut für Molekularbiologie, OE5250, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
6
Department of Cell & Developmental Biology, University of Illinois, Urbana, IL, USA; Institute for Genomic Biology, University of Illinois, Urbana, IL, USA. Electronic address: ljstubbs@illinois.edu.

Abstract

The vertebrate T-box transcription factor gene Tbx18 performs a vital role in development of multiple organ systems. Tbx18 insufficiency manifests as recessive phenotypes in the upper urinary system, cardiac venous pole, inner ear, and axial skeleton; homozygous null mutant animals die perinatally. Here, we report a new regulatory mutation of Tbx18, a reciprocal translocation breaking 78kbp downstream of the gene. 12Gso homozygotes present urinary and vertebral defects very similar to those associated with Tbx18-null mutations, but 12Gso is clearly not a global null allele since homozygotes survive into adulthood. We show that 12Gso down-regulates Tbx18 expression in a manner that is both spatially- and temporally-specific; combined with other data, the mutation points particularly to the presence of an essential urogenital enhancer located near the translocation breakpoint site. In support of this hypothesis, we identify a distal enhancer element, ECR1, which is active in developing urogenital and other tissues; we propose that disruption of this element leads to premature loss of Tbx18 function in 12Gso mutant mice. These data reveal a long-range regulatory architecture extending far downstream of Tbx18, identify a novel and likely essential urogenital enhancer, and introduce a new tool for dissecting postnatal phenotypes associated with dysregulation of Tbx18.

KEYWORDS:

Chromosome translocation; Regulatory mutation; T-box transcription factor; Urogenital development

PMID:
24854998
PMCID:
PMC4104242
DOI:
10.1016/j.ydbio.2014.05.010
[Indexed for MEDLINE]
Free PMC Article
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