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Danny Huylebroeck

Publications and source records attributed to Danny Huylebroeck.

25 records · Page 2Linked to original sources
PubMed2003

Generation of a floxed allele of Smad5 for cre-mediated conditional knockout in the mouse.

Smad5 is a member of the Smad family of intracellular mediators of BMP signals and in endothelial cells of TGF-beta signals. We and others previously showed that loss of Smad5 in the mouse results in embryonic lethality (between E9.5-E11.5) due to multiple embryonic and extraembryonic defects. To circumvent the early embryonic lethality and to allow tissue- and time-specific Smad5 inactivation, we created a conditional Smad5 allele in the mouse. Floxed Smad5 (Smad5(flE2,Neo/flE2,Neo)) mice were generated in which both exon2 and the Neo-cassette were flanked by loxP sites. Here we demonstrate that embryos with ubiquitous Cre-mediated deletion of Smad5 (Smad5(flDeltaE2/flDeltaE2)) phenocopy the conventional Smad5 knockout mice. Smad5(flE2/flE2) mice are now available and will be a valuable tool to analyze the role of Smad5 beyond its crucial early embryonic function throughout development and postnatal life.

Alleles↗
PubMed2003

Organization of the mouse Zfhx1b gene encoding the two-handed zinc finger repressor Smad-interacting protein-1.

SIP1, a member of the deltaEF1 family of two-handed zinc finger transcriptional repressors, has been identified as a Smad-binding protein. Recently, mutations in the human SIP1 gene (ZFHX1B) have been implicated in Hirschsprung disease. Here we document extensively the structure and transcriptional pattern of the mouse SIP1 gene (Zfhx1b) and compare it to homologues from other species. The overall structure of Zfhx1b is highly similar to that of the deltaEF1 gene (Zfhx1a), confirming their close evolutionary relationship. In contrast to Zfhx1a, the 5' untranslated region of the SIP1-encoding mouse gene is very complex and includes several alternative exons. The corresponding 5'-UTR splicing pattern seems to be conserved between species and suggests a role in its transcriptional and/or translational regulation. The gene also codes for an antisense transcript that is highly conserved between human and mouse.

Alternative Splicing↗
PubMed2002

Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3.

Receptors for bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGFbeta) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Here, we used a Cre/lox system for cardiac myocyte-specific deletion of the type IA BMP receptor, ALK3. ALK3 was specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 was specifically deficient in expressing TGFbeta2, an established paracrine mediator of cushion morphogenesis. Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis.

Animals↗
PubMed2002

Dynamic regulation of Brachyury expression in the amphibian embryo by XSIP1.

Xenopus Brachyury (Xbra) plays a key role in mesoderm formation during early development. One factor thought to be involved in the regulation of Xbra is XSIP1, a zinc finger/homeodomain-like DNA-binding protein that belongs to the deltaEF1 family of transcriptional repressors. We show here that Xbra and XSIP1 are co-expressed at the onset of gastrulation, but that expression subsequently refines such that Xbra is expressed in prospective mesoderm and XSIP1 in anterior neurectoderm. This refinement of the expression patterns of the two genes is due in part to the ability of XSIP1 to repress expression of Xbra. This repression is highly specific, in the sense that XSIP1 does not repress the expression of other regionally expressed genes in the early embryo, and that other members of the family to which XSIP1 belongs, such as deltaEF1 and its Xenopus homologue ZEB, cannot regulate Xbra expression. The function of XSIP1 was studied further by making an interfering construct comprising the open reading frame of XSIP1 fused to the VP16 transactivation domain. Experiments using this chimeric protein suggest that XSIP1 is required for normal gastrulation movements to occur and for the development of the anterior neural plate.

Animals↗
PubMed2002

Complex Smad-dependent transcriptional responses in vertebrate development and human disease.

Smad proteins mediate genomic responses to polypeptides of the transforming growth factor type beta (TGF-beta) family, affecting cellular proliferation and differentiation, adhesion, and death. Members of one class of these Smad proteins, the receptor-regulated Smads or R-Smads, accumulate in the nucleus on their activation by ligand-bound complexes of serine-threonine kinase receptors at the cell surface. These effector proteins then participate directly in the regulation of gene expression by binding to DNA, interacting with transcription factors, and recruiting corepressors or coactivators to specific promoters. Although many nuclear Smad-interacting factors were isolated during the last 3 years, the field has recently taken a step beyond the characterization of the activity of these Smad-containing complexes on gene expression in vitro, as it addresses now their contribution to many processes in vivo. We have selected examples of such recent progress to illustrate the remarkable variation in the molecular mechanisms underlying Smad-dependent signaling depending on the non-Smad partner in the nucleus and their relevance to normal embryogenesis and consequences of their deregulation in human disorders and pathology.

Animals↗
PubMedDate not supplied

Smads and chromatin modulation.

Smad proteins are critical intracellular effector proteins and regulators of transforming growth factor type beta (TGFbeta) modulated gene transcription. They directly convey signals that initiate at ligand-bound receptor complexes and end in the nucleus with changes in programs of gene expression. Activated Smad proteins seem to recruit chromatin modifying proteins to target genes besides cooperating with DNA-bound transcription factors. We survey here the current and still emerging knowledge on Smad-binding factors, and their different mechanisms of chromatin modification in particular, in Smad-dependent TGFbeta signaling.

Animals↗