Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation

Habets, Petra E.M.H.; Moorman, Antoon F.M.; Clout, Danielle E.W.; Roon, Marian A. van; Lingbeek, Merel; Lohuizen, Maarten van; Campione, Marina; Christoffels, Vincent M.

doi:10.1101/gad.222902

Cited by 324 publications

(376 citation statements)

References 60 publications

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“…Tbx2 forms a complex with Nkx2-5͞Csx on the site containing a T-box factor, located at position Ϫ250 bp, and an NK binding element, located at position Ϫ259 bp, within the ANF promoter and represses ANF promoter activity. In vivo inactivation of either site, such as AAGT of the NK binding element mutated to CCTC, eliminated the repression (50). These in vitro binding and in vivo functional studies indicate that the NK binding elements that are found in most of the known functional NK target sites are necessary either with or without cofactors.…”

Section: Discussionmentioning

confidence: 81%

Sequence-specific DNA binding by the vnd/NK-2 homeodomain of Drosophila

Wang

Chmelik²,

Nirenberg³

2002

Proc. Natl. Acad. Sci. U.S.A.

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The ventral nervous system defective (vnd)͞NK-2 homeodomain and some flanking amino acid residues were expressed in Escherichia coli, purified to homogeneity, and the protein was covalently coupled to Sepharose. Oligodeoxynucleotides that contained 16-bp random sequences were purified by vnd͞NK-2 affinity column chromatography, cloned, and sequenced. The consensus nucleotide sequence of the vnd͞NK-2 homeodomain binding site was shown to be T(T͞C)AAGTG(G͞C). The apparent equilibrium dissociation constant (KD) of the vnd͞NK-2 homeodomain for the consensus sequence is 1.9 ؋ 10 ؊10 M. In addition, results of competition between oligodeoxynucleotides for binding to the vnd͞NK-2 homeodomain and determination of the apparent KD values of oligodeoxynucleotides that differ from the consensus sequence by only a single base pair demonstrate that the four central nucleotides, AAGT, in this sequence play a major role in determining the affinity of binding.homeobox ͉ DNA binding site ͉ neurobiology H omeodomain (HD) proteins that are involved in sequencespecific recognition of DNA are transcription factors regulating multiple genes during development (1, 2). They use a helix-turn-helix motif to contact DNA in the major groove and an N-terminal arm to contact DNA in the minor groove (3, 4). HDs of some homeotic proteins in Drosophila (Hom) and mammals (Hox A-D) recognize a TAAT core (1). Hox proteins regulate developmental pathways as monomers (5, 6), but a few bind to cofactors, thereby increasing the DNA-binding specificity (7). The Drosophila ventral nervous system defective (vnd)͞NK-2 is an HD-containing protein (8, 9) that initiates neural development in the ventral column of neuroectoderm that gives rise to part of the ventral nerve cord in embryos (10, 11). Dichaete acts in concert with vnd͞NK-2 and intermediate neuroblasts defective to regulate cell fate and neuroblast formation (12). Regulation of vnd͞NK-2 expression is required for both neural and glial specification (13). The three-dimensional structure of the vnd͞NK-2 HD and its interaction with a target oligodeoxynucleotide (oligonucleotide) have been reported (14-17). Site mutations (single, double, or triple sites) involving Tyr-54 (Y54M) all showed a decrease of one order of magnitude in their binding affinities to the vnd͞NK-2 consensus DNA binding site (18). The NK-2 gene family now has been found in diverse phyla and has been shown to play important roles in organogenesis during development. These include vnd͞NK-2 (9, 10, 19, 20), Nkx2-1͞TTF1 (21, 22), Nkx2-2 (21), Nkx2-9 (23), or Nkx6-1 (24) for the nervous system; Tinman͞NK-4 (25), 27), for the heart; Nkx2-5͞Csx or Nkx2-6 for the pharynx (29); Nkx2-1͞TTF-1 for the thyroid and the lung (30); Nkx2-2 for pancreatic ␤ cells (31); Nkx2-8 for the liver (32); and Nkx5-1 for inner ear (33). An orphan homeobox mouse gene Hox11, which was proposed to belong to the NK family (33), controls the genesis of the spleen (34). Nkx3-1 is expressed in many tissues in the embryo; the expression is restricted primarily to the ...

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Section: Discussionmentioning

confidence: 81%

Sequence-specific DNA binding by the vnd/NK-2 homeodomain of Drosophila

Wang

Chmelik²,

Nirenberg³

2002

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, TBX1 haploinsufficiency causes DiGeorge syndrome and TBX5 haploinsufficiency results in HoltOram syndrome 9,10 . Targeted mutagenesis or knockdown of the genes encoding the T-box transcription factors demonstrates that Tbx1, Tbx2, Tbx3, Tbx5 (Tbx5a in zebrafish), Tbx18 and Tbx20 play essential roles during cardiac development in the mice or zebrafish [11][12][13][14][15][16][17][18][19] .…”

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confidence: 99%

Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish

Tong

et al. 2014

Nat Commun

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The T-box transcription factor Tbx5 (Tbx5a in zebrafish) plays a crucial role in the formation of cardiac chambers in a dose-dependent manner. Its deregulation leads to congenital heart disease. However, little is known regarding its regulation. Here we isolate a zebrafish mutant with heart malformations, called 34c. The affected gene is identified as kctd10, a member of the potassium channel tetramerization domain (KCTD)-containing family. In the mutant, the expressions of the atrioventricular canal marker genes, such as tbx2b, hyaluronan synthase 2 (has2), notch1b and bmp4, are changed. The knockdown of tbx5 rescues the ectopic expression of has2, and knockdown of either tbx5a or has2 alleviates the heart defects. We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. Our results reveal a new essential factor for cardiac development and suggest that KCTD10 could be considered as a new causative gene of congenital heart disease.

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“…How Irx4 promotes ventricular muscle gene expression is not yet known, nor do we understand how expression differences within subdomains of individual chambers are established. In addition, the interplay of the cardiac T-box transcription factors, Tbx2, -3, and -5, have been implicated in the regulation of the chamber-myocardium gene expression, although the precise mechanisms are still to be determined (Habets et al, 2002;Christoffels et al, 2004;Hoogaars et al, 2004). However, despite these advances, there remains much uncertainty surrounding the relationship between cardiac muscle formation and the generation of the distinct functions of the mature chambers of the vertebrate heart.…”

Section: Introductionmentioning

confidence: 99%

The MLC1v gene provides a transgenic marker of myocardium formation within developing chambers of the Xenopus heart

Smith¹,

Ataliotis²,

Kotecha³

et al. 2005

Developmental Dynamics

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Many details of cardiac chamber morphogenesis could be revealed if muscle fiber development could be visualized directly within the hearts of living vertebrate embryos. To achieve this end, we have used the active promoter of the MLC1v gene to drive expression of green fluorescent protein (GFP) in the developing tadpole heart. By using a line of Xenopus laevis frogs transgenic for the MLC1v-EGFP reporter, we have observed regionalized patterns of muscle formation within the ventricular chamber and maturation of the atrial chambers, from the onset of chamber formation through to the adult frog. In f1 generation MLC1v-EGFP animals, promoter activity is first detected within the looping heart tube and delineates the forming ventricular chamber and proximal outflow tract throughout their development.

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Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation

Cited by 324 publications

References 60 publications

Sequence-specific DNA binding by the vnd/NK-2 homeodomain of Drosophila

Sequence-specific DNA binding by the vnd/NK-2 homeodomain of Drosophila

Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish

The MLC1v gene provides a transgenic marker of myocardium formation within developing chambers of the Xenopus heart

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