BCL6 Canalizes Notch-Dependent Transcription, Excluding Mastermind-like1 from Selected Target Genes during Left-Right Patterning

Sakano, Daisuke; Kato, Akira; Parikh, Nisarg; McKnight, Kelly; Terry, Doris E.; Stefanovic, Branko; Kato, Yoichi

doi:10.1016/j.devcel.2009.12.023

Cited by 52 publications

(67 citation statements)

References 68 publications

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“…Such blockage could result from either the failure to completely displace corepressors from Su(H) or if there are proteins specifically bound to the ac promoter that prevent formation of the Su(H)/NICD/Mam ternary complex. The latter mechanism is similar to a corepression mechanism recently described for the cell-specific regulation of the Notch target gene Pitx2 in Xenopus (37). We previously showed that coactivation by Mam is promoter specific and that Mam does not coactivate the ac promoter, even if an SPS element is present (6).…”

Section: Fig 4 Recruitment Of Su(h)mentioning

confidence: 79%

Differential Regulation of Transcription through Distinct Suppressor of Hairless DNA Binding Site Architectures during Notch Signaling in Proneural Clusters

Cave

Caudy

2011

Molecular and Cellular Biology

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In Drosophila melanogaster, achaete (ac) and m8 are model basic helix-loop-helix activator (bHLH A) and repressor genes, respectively, that have the opposite cell expression pattern in proneural clusters during Notch signaling. Previous studies have shown that activation of m8 transcription in specific cells within proneural clusters by Notch signaling is programmed by a "combinatorial" and "architectural" DNA transcription code containing binding sites for the Su(H) and proneural bHLH A proteins. Here we show the novel result that the ac promoter contains a similar combinatorial code of Su(H) and bHLH A binding sites but contains a different Su(H) site architectural code that does not mediate activation during Notch signaling, thus programming a cell expression pattern opposite that of m8 in proneural clusters.In Drosophila melanogaster neurogenesis, the proneural basic helix-loop-helix activator (bHLH A) genes are initially expressed in clusters of adjacent cells called "proneural clusters" (Fig. 1A). Although each cell within the proneural cluster has the potential to adopt a neural cell fate, only one cell or a few cells within the cluster become a neural precursor cell (NPC). Subsequently, the expression of both the proneural bHLH A genes and several putative downstream "panneural" target genes are strongly upregulated in the NPC. In contrast, the expression of proneural and panneural gene is not upregulated in the non-NPCs.Notch signaling-mediated lateral inhibition is critical for repression of proneural bHLH A gene expression in the nonNPCs. Several effector genes for the lateral inhibition pathway in proneural clusters are in the Enhancer of split Complex [E(spl)-C]. The E(spl)-C bHLH repressor (bHLH R) genes (m3, m5, m7, m8, m␥, and m␦) are well-characterized effector genes for Notch signaling (4), and the E(spl)-C m4 and m␣ Bearded-like (Brd-like) genes have also been proposed to mediate lateral inhibition (2). The bHLH R proteins can repress proneural gene expression by binding to R sites in proneural gene regulatory regions (33,34,40) as well as physically interacting with the proneural proteins and blocking proneural autoactivation (15, 16). The Brd-like proteins physically interact with the Neuralized panneural protein and modulate intracellular processing of the Notch signaling ligand Delta (2).Activation of E(spl)-C gene transcription in proneural clusters is initially inhibited by a "default repression" mechanism that is mediated by the bifunctional protein Suppressor of Hairless [Su(H); also called CSL], which binds to S DNA binding sites (3,5,21,28). In the absence of Notch signaling, Su(H) mediates repression of these genes by recruiting specific corepressors, including Hairless (H), Groucho (Gro), and dCtBP ( Fig. 1B) (3, 30). However, once the NPC is established in proneural clusters, the Notch receptor becomes selectively activated in the non-NPCs, and Su(H)-mediated repression of the E(spl)-C genes in the non-NPCs is relieved. This derepression is due to the cleaved Notch intracellular d...

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Section: Fig 4 Recruitment Of Su(h)mentioning

confidence: 79%

Differential Regulation of Transcription through Distinct Suppressor of Hairless DNA Binding Site Architectures during Notch Signaling in Proneural Clusters

Cave

Caudy

2011

Molecular and Cellular Biology

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“…A considerable number of studies have reported complete absence of nodal, lefty, or pitx2 expression (Field et al, 2011; Oki et al, 2010; Sakano et al, 2010; Gaio et al, 1999; Takeuchi et al, 2007; Zhang et al, 2001; Yan et al, 1999; Tsukui et al, 1999; Collignon et al, 1996; Kramer-Zucker et al, 2005; Krebs et al, 2003; Pennekamp et al, 2002), with some reporting 100% absent expression for all three genes. What does complete absence of gene expression mean?…”

Section: Discussionmentioning

confidence: 99%

Laterality defects are influenced by timing of treatments and animal model

Vandenberg

2012

Differentiation

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The timing of when the embryonic left-right (LR) axis is first established and the mechanisms driving this process are subjects of strong debate. While groups have focused on the role of cilia in establishing the LR axis during gastrula and neurula stages, many animals appear to orient the LR axis prior to the appearance of, or without the benefit of, motile cilia. Because of the large amount of data available in the published literature and the similarities in the type of data collected across labs, I have examined relationships between the studies that do and do not implicate cilia, the choice of animal model, the kinds of LR patterning defects observed, and the penetrance of LR phenotypes. I found that treatments affecting cilia structure and motility had a higher penetrance for both altered gene expression and improper organ placement compared to treatments that affect processes in early cleavage stage embryos. I also found differences in penetrance that could be attributed to the animal models used; the mouse is highly prone to LR randomization. Additionally, the data were examined to address whether gene expression can be used to predict randomized organ placement. Using regression analysis, gene expression was found to be predictive of organ placement in frogs, but much less so in the other animals examined. Together, these results challenge previous ideas about the conservation of LR mechanisms, with the mouse model being significantly different from fish, frogs and chick in almost every aspect examined. Additionally, this analysis indicates that there may be missing pieces in the molecular pathways that dictate how genetic information becomes organ positional information in vertebrates; these gaps will be important for future studies to identify, as LR asymmetry is not only a fundamentally fascinating aspect of development but also of considerable biomedical importance.

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“…Like in frog (Hilton et al, 2007;Sakano et al, 2010), BCoR mutations randomize LR asymmetry in human embryos (Ng et al, 2004;Hilton et al, 2007), but this does not occur in mouse (Ye et al, 1997;Yoshida et al, 1999). The loss of brain asymmetry observed in mouse mutants with ciliary dyskinesia (Kawakami et al, 2008) is not observed in human patients (Kennedy et al, 1999;Tanaka et al, 1999;McManus et al, 2004;Afzelius and Stenram, 2006).…”

Section: The Mouse As a Model For Mammalian Asymmetrymentioning

confidence: 94%

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

Vandenberg

Levin

2010

Developmental Dynamics

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Consistent laterality is a crucial aspect of embryonic development, physiology, and behavior. While strides have been made in understanding unilaterally expressed genes and the asymmetries of organogenesis, early mechanisms are still poorly understood. One popular model centers on the structure and function of motile cilia and subsequent chiral extracellular fluid flow during gastrulation. Alternative models focus on intracellular roles of the cytoskeleton in driving asymmetries of physiological signals or asymmetric chromatid segregation, at much earlier stages. All three models trace the origin of asymmetry back to the chirality of cytoskeletal organizing centers, but significant controversy exists about how this intracellular chirality is amplified onto cell fields. Analysis of specific predictions of each model and crucial recent data on new mutants suggest that ciliary function may not be a broadly conserved, initiating event in left-right patterning. Many questions about embryonic left-right asymmetry remain open, offering fascinating avenues for further research in cell, developmental, and evolutionary biology. Developmental Dynamics 239:3131-3146,

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BCL6 Canalizes Notch-Dependent Transcription, Excluding Mastermind-like1 from Selected Target Genes during Left-Right Patterning

Cited by 52 publications

References 68 publications

Differential Regulation of Transcription through Distinct Suppressor of Hairless DNA Binding Site Architectures during Notch Signaling in Proneural Clusters

Differential Regulation of Transcription through Distinct Suppressor of Hairless DNA Binding Site Architectures during Notch Signaling in Proneural Clusters

Laterality defects are influenced by timing of treatments and animal model

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

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