Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43

Boogerd, Cornelis J.; Wong, Leeyean; Christoffels, Vincent M.; Klarenbeek, Meinke; Ruijter, Jan M.; Moorman, Antoon F.M.; Barnett, Phil

doi:10.1093/cvr/cvn049

Cited by 78 publications

(59 citation statements)

References 45 publications

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“…TBX2 has been shown in embryonic tissues to cooperate with transcription factors, such as Msx1/ Msx2 or NKX2.5, with promoter binding sites adjacent to T-box sites to regulate genes such as Connexin43 and atrial natriuretic factor, respectively (Habets et al, 2002;Boogerd et al, 2008). To the best of our knowledge, our study is the first to show that TBX2 is able to target genes independent of a T-box binding element through EGR1.…”

Section: Discussionmentioning

confidence: 58%

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

et al. 2010

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T-box 2 (TBX2) is a transcription factor involved in mammary development and is known to be overexpressed in a subset of aggressive breast cancers. TBX2 has previously been shown to repress growth control genes such as p14 ARF and p21 WAF1/cip1 . In this study we show that TBX2 drives proliferation in breast cancer cells and this is abrogated after TBX2 small interfering RNA (siRNA) knockdown or after the expression of a dominant-negative TBX2 protein. Using microarray analysis we identified a large cohort of novel TBX2-repressed target genes including the breast tumour suppressor NDRG1 (N-myc downregulated gene 1). We show that TBX2 targets NDRG1 through a previously undescribed mechanism involving the recruitment of early growth response 1 (EGR1). We show EGR1 is required for the ability of TBX2 to repress NDRG1 and drive cell proliferation. We show that TBX2 interacts with EGR1 and that TBX2 requires EGR1 to target the NDRG1 proximal promoter. Abrogation of either TBX2 or EGR1 expression is accompanied by the upregulation of cell senescence and apoptotic markers. NDRG1 can recapitulate these effects when transfected into TBX2-expressing cells. Together, these data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue.

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Section: Discussionmentioning

confidence: 58%

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

et al. 2010

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“…6A). Furthermore, known Msx1 targets in the promoters of connexin 43 (Cx43; also known as Gja1) (Boogerd et al, 2008) and Stra8.2 (Le Bouffant et al, 2011) were not amplified (Fig. 6A), consistent with the absence of heart primordium or developing gonads from the samples analyzed.…”

Section: Msx1mentioning

confidence: 52%

Msx1 and Msx2 act as essential activators of Atoh1 expression in the murine spinal cord

et al. 2014

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Dorsal spinal neurogenesis is orchestrated by the combined action of signals secreted from the roof plate organizer and a downstream transcriptional cascade. Within this cascade, Msx1 and Msx2, two homeodomain transcription factors (TFs), are induced earlier than bHLH neuralizing TFs. Whereas bHLH TFs have been shown to specify neuronal cell fate, the function of Msx genes remains poorly defined. We describe dramatic alterations of neuronal patterning in Msx1/Msx2 double-mutant mouse embryos. The most dorsal spinal progenitor pool fails to express the bHLH neuralizing TF Atoh1, which results in a lack of Lhx2-positive and Barhl2-positive dI1 interneurons. Neurog1 and Ascl1 expression territories are dorsalized, leading to ectopic dorsal differentiation of dI2 and dI3 interneurons. In proportion, the amount of Neurog1-expressing progenitors appears unaffected, whereas the number of Ascl1-positive cells is increased. These defects occur while BMP signaling is still active in the Msx1/ Msx2 mutant embryos. Cell lineage analysis and co-immunolabeling demonstrate that Atoh1-positive cells derive from progenitors expressing both Msx1 and Msx2. In vitro, Msx1 and Msx2 proteins activate Atoh1 transcription by specifically interacting with several homeodomain binding sites in the Atoh1 3′ enhancer. In vivo, Msx1 and Msx2 are required for Atoh1 3′ enhancer activity and ChIP experiments confirm Msx1 binding to this regulatory sequence. These data support a novel function of Msx1 and Msx2 as transcriptional activators. Our study provides new insights into the transcriptional control of spinal cord patterning by BMP signaling, with Msx1 and Msx2 acting upstream of Atoh1.

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“…The inactivation of Tbx2, either globally or specifically in the developing myocardium, thus results in malformation of the annulus fibrosus and the ectopic expression of chamber genes in the AVC, leading to the formation of ectopic conductive AV pathways, reminiscent of the situation observed in Wolff-Parkinson-White syndrome of ventricular pre-excitation (Aanhaanen et al, 2011). Tbx2 and Tbx3 interact with the musclesegment homeobox transcription factor Msx2, which is expressed in the AVC, to suppress the expression of Cx43 directly (Boogerd et al, 2008;Chen et al, 2008). They also compete with Tbx5 both for binding to T-box elements in target genes, such as Nppa and Cx40 (Hoogaars et al, 2004;van den Boogaard et al, 2012) , and for interaction with Nkx2-5 to repress Nppa in the AVC (Habets et al, 2002).…”

Section: Transcriptional Regulation Of Avc and Avn Developmentmentioning

confidence: 99%

The formation and function of the cardiac conduction system

2016

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The cardiac conduction system (CCS) consists of distinctive components that initiate and conduct the electrical impulse required for the coordinated contraction of the cardiac chambers. CCS development involves complex regulatory networks that act in stage-, tissue-and dose-dependent manners, and recent findings indicate that the activity of these networks is sensitive to common genetic variants associated with cardiac arrhythmias. Here, we review how these findings have provided novel insights into the regulatory mechanisms and transcriptional networks underlying CCS formation and function.

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Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43

Abstract: Msx1 and Msx2 can function in concert with the T-box proteins to suppress Cx43 and other working myocardial genes.

Cited by 78 publications

References 45 publications

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

Msx1 and Msx2 act as essential activators of Atoh1 expression in the murine spinal cord

The formation and function of the cardiac conduction system

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