Isolation and characterization of <i>Xenopus Hey‐1</i>: A downstream mediator of Notch signaling

Rones, Melissa S.; Woda, Juliana M.; Mercola, Mark; McLaughlin, Kelly A.

doi:10.1002/dvdy.10192

Cited by 15 publications

(14 citation statements)

References 31 publications

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“…Both Hey genes can be Notch regulated: reduction of Hey1 and Hey2 mRNA occurs in Notch1 -/- (Leimeister et al, 2000) and Dll3 -/- (Dunwoodie et al, 2002) mutant mice, and both Hey1 and Hey2 genes have binding sites for CSL and can be upregulated in response to Notch pathway activators such as N1 icd (Iso et al, 2001;Maier and Gessler, 2000;Nakagawa et al, 2000). Nonetheless, Notch-independent transcription of Hey1 and Hey2 genes has also been reported (Iso et al, 2001;Rones et al, 2002), pointing to the existence of tissuespecific factors that modulate Hey gene responsiveness to CSL and the Notch pathway.…”

Section: Discussionmentioning

confidence: 99%

Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors

et al. 2006

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Mutations in Notch2, Jagged1 or homologs of the Hairy-related transcriptional repressor Hey2 cause congenital malformations involving the non-chamber atrioventricular canal (AVC) and inner curvature (IC) regions of the heart, but the underlying mechanisms have not been investigated. By manipulating signaling directly within the developing chick heart, we demonstrated that Notch2, Hey1 and Hey2 initiate a signaling cascade that delimits the non-chamber AVC and IC regions. Specifically, misactivation of Notch2 signaling, or misexpression of either Hey1 or Hey2, repressed Bmp2. Because Jagged (also known as Serrate in non-mammalian species) ligands were found to be present in prospective chamber myocardium, these data support the model that Notch2 and Hey proteins cause the progressive restriction of Bmp2 expression to within the developing AVC and IC, where it is essential for differentiation. Misactivation or inhibition of Notch2 specifically induced or inhibited Hey1, respectively, but these manipulations did not affect Hey2, implicating Hey1 as the direct mediator of Notch2. Bmp2 within the developing AVC and IC has been shown to induce Tbx2, and we found that Tbx2 misexpression inhibited the expression of both Hey1 and Hey2. Tbx2, therefore, is envisaged to constitute a feedback loop that sharpens the border with the developing AVC and IC by delimiting Hey gene expression to within prospective chamber regions. Analysis of the loss-of-function phenotype in mouse embryos homozygous for targeted disruption of Hey2 revealed an expanded AVC domain of Bmp2. Similarly, zebrafish gridlock (Hey2 homolog) mutant embryos showed ectopic expression of Bmp4, which normally marks AVC myocardium in this species. Thus, Hey pathway regulation of cardiac Bmp appears to be an evolutionarily conserved mechanism to delimit AVC and IC fate, and provides a potential mechanistic explanation for cardiac malformations caused by mutations in Serrate/Jagged1 and Notch signaling components.

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Section: Discussionmentioning

confidence: 99%

Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors

et al. 2006

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“…esr9, esr10 and Xhairy2b are, like XHRT1, responsive to Notch signaling in the developing pronephros The XHRT1 gene has previously been shown to be responsive to Notch signaling in the pronephros (Rones et al, 2002). We investigated whether Notch signaling also affects the expression of the other bHLH-O genes.…”

Section: Research Articlementioning

confidence: 98%

“…In Xenopus, the XHRT1 gene (also named Hey1/HERP2/Hesr-1/CHF2), encoding a downstream basic helix-loop-helix Orange (bHLH-O) mediator of Notch signaling, has been shown to be expressed in numerous tissues during development, including the pronephros, and to be responsive to Notch signaling (Rones et al, 2002;Pichon et al, 2002). XHRT1 is a member of the HRT subfamily of bHLH-O proteins that forms heterodimers with hairy proteins through the bHLH-O and downstream sequences, and represses transcription in a groucho-independent manner (Iso et al, 2003;Taelman et al, 2004;Pichon et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The Notch-effectorHRT1gene plays a role in glomerular development and patterning of theXenopuspronephros anlagen

et al. 2006

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Notch signaling has been shown to play a role in cell fate decisions in the Xenopus pronephros anlagen. Here, we show that the Xenopus Hairy-related transcription factor (HRT) gene XHRT1, and the Hairy/Enhancer of split (HES) genes Xhairy1, Xhairy2b, esr9 and esr10, have distinct restricted dynamic expression patterns during pronephros development, and that their expression is regulated by Notch. XHRT1, which is the earliest and strongest gene expressed in the pronephric region, is initially transcribed predominantly in the forming glomus, where it is downregulated by antisense morpholino oligonucleotide inhibition of xWT1. Later, it is activated in the most dorsoanterior part of the pronephros anlagen that gives rise to the proximal tubules. In agreement with this dynamic expression profile, we found that early activation of Notch favors glomus, whereas only later activation promotes proximal tubule formation. We show that, among the bHLH-O factors tested, only XHRT1 efficiently inhibits distal tubule and duct formation, and that only its translational inhibition causes a reduction of the expression of proximal tubule and glomus markers. Using domain swap experiments, we found that the XHRT1 C-terminal region is crucial for its activity. Together, our results provide evidence that XHRT1 plays an important role in glomerular development and early proximodistal patterning that is distinct from those of the other pronephric bHLH repressors.

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“…4D). This result is surprising because single injections of either wnt4 mRNA or su (H) DBM mRNA reduced slc5a2 expression ( Fig hrt1 acts upstream of wnt4 in the pronephros The Hairy-related transcription factor gene hrt1, encodes a downstream mediator of Notch signalling that has been shown to be responsive to Notch signalling in numerous tissues (Pichon et al, 2002;Rones et al, 2002). HRT-1 has been shown to regulate glomus formation and patterning of the pronephros anlagen (Taelman et al, 2006).…”

Section: Research Article Notch Signalling Controls Pronephrogenesismentioning

confidence: 99%

“…In Drosophila, such post-translational modifications promote Notch interactions with its Delta ligand (Bruckner et al, 2000;Moloney et al, 2000). Previous studies have highlighted roles for downstream Notch effector genes during proximal pronephrogenesis (Rones et al, 2002;Taelman et al, 2006), yet an understanding for how Notch signalling is regulated, and how this regulation affects pronephros development, has not been investigated. If X. laevis homologues of the Drosophila fringe gene, lunatic fringe (lfng) and radical fringe (rfng), were temporally and spatially expressed appropriately in the pronephros, this finding would further understanding of the mechanism by which Notch signalling is regulated in the proximal pronephros.…”

Section: Overexpression Of Notch-icd Inhibits Formation Of the Lateramentioning

confidence: 99%

Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros

Naylor

Jones

2009

Development

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Previous studies have highlighted a role for the Notch signalling pathway during pronephrogenesis in the amphibian Xenopus laevis, and in nephron development in the mammalian metanephros, yet a mechanism for this function remains elusive. Here, we further the understanding of how Notch signalling patterns the early X. laevis pronephros anlagen, a function that might be conserved in mammalian nephron segmentation. Our results indicate that early phase pronephric Notch signalling patterns the medio-lateral axis of the dorso-anterior pronephros anlagen, permitting the glomus and tubules to develop in isolation. We show that this novel function acts through the Notch effector gene hrt1 by upregulating expression of wnt4. Wnt-4 then patterns the proximal pronephric anlagen to establish the specific compartments that span the medio-lateral axis. We also identified pronephric expression of lunatic fringe and radical fringe that is temporally and spatially appropriate for a role in regulating Notch signalling in the dorso-anterior region of the pronephros anlagen. On the basis of these results, along with data from previous publications, we propose a mechanism by which the Notch signalling pathway regulates a Wnt-4 function that patterns the proximal pronephric anlagen.

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Isolation and characterization of Xenopus Hey‐1: A downstream mediator of Notch signaling

Cited by 15 publications

References 31 publications

Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors

Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors

The Notch-effectorHRT1gene plays a role in glomerular development and patterning of theXenopuspronephros anlagen

Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros

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