Michael Caudy - Academia.edu (original) (raw)

Papers by Michael Caudy

Genes & Development, Jul 1, 1998

Molecular and Cellular Biology, Jun 1, 1996

Hairy-related proteins include the Drosophila Hairy and Enhancer of Split proteins and mammalian ... more Hairy-related proteins include the Drosophila Hairy and Enhancer of Split proteins and mammalian Hes proteins. These proteins are basic helix-loop-helix (bHLH) transcriptional repressors that control cell fate decisions such as neurogenesis or myogenesis in both Drosophila melanogaster and mammals. Hairy-related proteins are site-specific DNA-binding proteins defined by the presence of both a repressor-specific bHLH DNA binding domain and a carboxyl-terminal WRPW (Trp-Arg-Pro-Trp) motif. These proteins act as repressors by binding to DNA sites in target gene promoters and not by interfering with activator proteins, indicating that these proteins are active repressors which should therefore have specific repression domains. Here we show the WRPW motif to be a functional transcriptional repression domain sufficient to confer active repression to Hairy-related proteins or a heterologous DNA-binding protein, Gal4. This motif was previously shown to be necessary for interactions with Groucho, a genetically defined corepressor for Drosophila Hairy-related proteins. Here we show that the WRPW motif is sufficient to recruit Groucho or the TLE mammalian homologs to target gene promoters. We also show that Groucho and TLE proteins actively repress transcription when directly bound to a target gene promoter and identify a novel, highly conserved transcriptional repression domain in these proteins. These results directly demonstrate that Groucho family proteins are active transcriptional corepressors for Hairy-related proteins and are recruited by the 4-amino acid protein-protein interaction domain, WRPW.

Current Biology, 2005

pattern of functional DNA binding sites within a module represents a "transcription regulatory co... more pattern of functional DNA binding sites within a module represents a "transcription regulatory code" (reviewed Department of Neurology and Neuroscience 525 East 68th Street in [2, 3]). Several "combinatorial" transcription codes con-New York, New York 10021 taining only a combination of specific DNA binding sites in an apparently random order have been studied [4-7] (and reviewed in [8]). However, transcription codes with Summary specific organizational or architectural features-the order, orientation, and spacing of binding sites-have Background: Cell-specific gene regulation is often conbeen less examined [3, 9, 10]. Important questions in trolled by specific combinations of DNA binding sites in the field are whether architectural features generally target enhancers or promoters. A key question is function as key parameters of tissue-or cell-specific whether these sites are randomly arranged or if there is transcription codes [9], and if so, what molecular mechaan organizational pattern or "architecture" within such nisms translate the code into a specific gene transcripregulatory modules. During Notch signaling in Drosophtion pattern? ila proneural clusters, cell-specific activation of certain Transcription regulatory codes provide the heritable Notch target genes is known to require transcriptional genetic programs that control precise patterns of gene synergy between the Notch intracellular domain (NICD) expression during development and normal cell physiolcomplexed with CSL proteins bound to "S" DNA sites ogy. Understanding such codes is important because and proneural bHLH activator proteins bound to nearby it potentially allows the identification of any or all of the "A" DNA sites. Previous studies have implied that arbispecific targets for any set of transcription factors that trary combinations of S and A DNA binding sites (an function combinatorially in a particular regulatory path-"SϩA" transcription code) can mediate the Notchway. In addition, knowing such codes can potentially proneural transcriptional synergy. allow accurate prediction of specific expression pat-Results: By contrast, we show that the Notch-proneural terns and regulators for any gene of interest. transcriptional synergy critically requires a particular One important goal for transcription code analysis is DNA site architecture ("SPS"), which consists of a pair to understand cell-specific gene expression in response of specifically-oriented S binding sites. Native and synto Notch signaling. The Notch signaling pathway is an thetic promoter analysis shows that the SPS architecintegral part of intercellular communication during neuture in combination with proneural A sites creates a rogenesis and other metazoan developmental prominimal DNA regulatory code, "SPSϩA", that is both cesses [11-17]. Restriction of neural cell fates by lateral sufficient and critical for mediating the Notch-proneural inhibition, a mechanism by which a cell can repress a synergy. Transgenic Drosophila analysis confirms the developmental fate in neighboring cells, is one such SPS orientation requirement during Notch signaling in Notch-regulated process [11, 18]. In both Drosophila proneural clusters. We also present evidence that CSL and vertebrates, Notch-mediated lateral inhibition is acinteracts directly with the proneural Daughterless procomplished, in part, by transcriptional activation of sevtein, thus providing a molecular mechanism for this eral basic helix-loop-helix repressor (bHLH R) genes synergy. in the Drosophila Enhancer of split complex [E(spl)-C] Conclusions: The SPS architecture functions to medi-(reviewed in [14, 19]) and the homologous HES {Hairy/ ate or enable the Notch-proneural transcriptional E(spl)} genes in vertebrates (reviewed in [20]). synergy which drives Notch target gene activation in Notch activates transcription of bHLH R genes via CSL specific cells. Thus, SPSϩA is an architectural DNA tranprotein DNA binding sites ("CSL": mammalian CBF-1, scription code that programs a cell-specific pattern of Drosophila Suppressor of Hairless and C. elegans gene expression. LAG-1) [21-24]. (Hereafter, CSL DNA binding sites are referred to as S sites.) Upon signal reception and cleav-Introduction age from its transmembrane domain, the Notch intracellular domain (NICD) enters the nucleus where it com-The spatial and temporal expression patterns of genes plexes with CSL proteins and displaces corepressor are controlled by distinct modules of transcription factor proteins (reviewed in [15, 16, 25-27]). Following the forbinding sites found in enhancer and promoter regions mation of this NICD/CSL protein "binary complex," addi-[1]. Enhancer and promoter modules consist of a partictional coactivator proteins, such as Mastermind (Mam), ular combination of DNA binding sites that together meare recruited to form multiprotein complexes that facilitate activation of gene transcription [28-34]. These multiprotein "Notch complexes" synergistically activate

BioEssays, Apr 1, 1998

Hairy-related proteins are a distinct subfamily of basic helix-loop-helix (bHLH) proteins that ge... more Hairy-related proteins are a distinct subfamily of basic helix-loop-helix (bHLH) proteins that generally function as DNA-binding transcriptional repressors. These proteins act in opposition to bHLH transcriptional activator proteins such as the proneural and myogenic proteins; together, the activator and repressor genes that encode these proteins have co-evolved as a regulatory gene ''cassette'' or ''module'' for controlling cell fate decisions. In the development of the Drosophila peripheral nervous system, Hairy-related genes function at multiple steps during neurogenesis, for example, as positional information genes that establish the ''prepattern'' that controls where ''proneural cluster'' equivalence groups will form, and later as nuclear effectors of the Notch signaling pathway to ''single out'' individual precursor cells within the equivalence group. Hairy-related genes also function in the establishment and restriction of other types of equivalence groups, such as those for muscle and Malphigian tubule precursors. This general function in cell fate specification has been conserved from Drosophila to vertebrates and has implications for human disease pathogenesis.

The Journal of Neuroscience, Feb 1, 1986

Biochemical and Biophysical Research Communications, Dec 1, 2008

Developmental Biology, Feb 1, 1987

Molecular and Cellular Biology, 2011

In Drosophila melanogaster, achaete (ac) and m8 are model basic helix-loop-helix activator (bHLH ... more 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.

The Journal of Neuroscience, Jun 1, 1986

Genes & Development, Dec 1, 1997

Molecular and Cellular Biology, 1996

Reactome - a curated knowledgebase of biological pathways, 2009

Reactome (http://www.reactome.org) is an expertauthored, peer-reviewed knowledgebase of human rea... more Reactome (http://www.reactome.org) is an expertauthored, peer-reviewed knowledgebase of human reactions and pathways that functions as a data mining resource and electronic textbook. Its current release includes 2975 human proteins, 2907 reactions and 4455 literature citations. A new entitylevel pathway viewer and improved search and data mining tools facilitate searching and visualizing pathway data and the analysis of user-supplied high-throughput data sets. Reactome has increased its utility to the model organism communities with improved orthology prediction methods allowing pathway inference for 22 species and through collaborations to create manually curated Reactome pathway datasets for species including Arabidopsis, Oryza sativa (rice), Drosophila and Gallus gallus (chicken). Reactome's data content and software can all be freely used and redistributed under open source terms. EXPANDED COVERAGE OF HUMAN PATHWAYS The current release of Reactome (version 26, September 2008) covers approximately 12.5% of 20 000 curated UniProt human proteins, a 2.7-fold increase over the last three years. Forty-six major domains of human

BMC Research Notes, 2009

Background: Cell-specific expression of a subset of Enhancer of split (E(spl)-C) genes in proneur... more Background: Cell-specific expression of a subset of Enhancer of split (E(spl)-C) genes in proneural clusters is mediated by synergistic interactions between bHLH A (basic Helix-Loop-Helix Activator) and Notch-signalling transcription complex (NTC) proteins. For a some of these E(spl)-C genes, such as m8, these synergistic interactions are programmed by an "SPS+A" transcription code in the cis-regulatory regions. However, the molecular mechanisms underlying this synergistic interaction between NTCs and proneural bHLH A proteins are not fully understood. Findings: Using cell transcription assays, we show that the N-terminal region of the Daughterless (Da) bHLH A protein is critical for synergistic interactions with NTCs that activate the E(spl)-C m8 promoter. These assays also show that this interaction is dependent on the specific inverted repeat architecture of Suppressor of Hairless (Su(H)) binding sites in the SPS+A transcription code. Using protein-protein interaction assays, we show that two distinct regions within the Da N-terminus make a direct physical interaction with the NTC protein Su(H). Deletion of these interaction domains in Da creates a dominant negative protein that eliminates NTC-bHLH A transcriptional synergy on the m8 promoter. In addition, over-expression of this dominant negative Da protein disrupts Notch-mediated lateral inhibition during mechanosensory bristle neurogenesis in vivo. Conclusion: These findings indicate that direct physical interactions between Da-N and Su(H) are critical for the transcriptional synergy between NTC and bHLH A proteins on the m8 promoter. Our results also indicate that the orientation of the Su(H) binding sites in the SPS+A transcription code are critical for programming the interaction between Da-N and Su(H) proteins. Together, these findings provide insight into the molecular mechanisms by which the NTC synergistically interacts with bHLH A proteins to mediate Notch target gene expression in proneural clusters.

Reactome - a curated knowledgebase of biological pathways, 2008

The contents of this document may be freely copied and distributed in any media, provided the aut... more The contents of this document may be freely copied and distributed in any media, provided the authors, plus the institutions, are credited, as stated under the terms of Creative Commons Attribution 4.0 International (CC BY 4.0) License. For more information see our license.

This article cites 64 articles, 37 of which can be accessed free

The Journal of Neuroscience, 1986

We thank Alma Toroian-Raymond for light-microscope histology and technical assistance, and Dr. Ma... more We thank Alma Toroian-Raymond for light-microscope histology and technical assistance, and Dr. Marty Shankland for critiquing the manuscript. Support was provided by NIH NS09074-14and NIH 2T32-GM07379. D.B. wasalso supported by an NIH Jacob Javits Award, and M.C. by an Einstein Fellowship for Developmental Neuroscience, from the University of California.