Biomedical subjects

David G McFadden

Publications and source records attributed to David G McFadden.

4 recordsLinked to original sources

PubMed2004

The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner.

The basic helix-loop-helix transcription factors Hand1 and Hand2 display dynamic and spatially restricted expression patterns in the developing heart. Mice that lack Hand2 die at embryonic day 10.5 from right ventricular hypoplasia and vascular defects, whereas mice that lack Hand1 die at embryonic day 8.5 from placental and extra-embryonic abnormalities that preclude analysis of its potential role in later stages of heart development. To determine the cardiac functions of Hand1, we generated mice harboring a conditional Hand1-null allele and excised the gene by cardiac-specific expression of Cre recombinase. Embryos homozygous for the cardiac Hand1 gene deletion displayed defects in the left ventricle and endocardial cushions, and exhibited dysregulated ventricular gene expression. However, these embryos survived until the perinatal period when they died from a spectrum of cardiac abnormalities. Creation of Hand1/2 double mutant mice revealed gene dose-sensitive functions of Hand transcription factors in the control of cardiac morphogenesis and ventricular gene expression. These findings demonstrate that Hand factors play pivotal and partially redundant roles in cardiac morphogenesis, cardiomyocyte differentiation and cardiac-specific transcription.

Alleles↗

PubMed2003

Galphaq and Galpha11 proteins mediate endothelin-1 signaling in neural crest-derived pharyngeal arch mesenchyme.

Endothelin-A (ET(A)) is a G-protein-coupled receptor expressed in the neural crest-derived mesenchyme of the pharyngeal arches during craniofacial development. Targeted deletion of the ET(A) receptor or its ligand endothelin-1 (ET-1) causes cleft palate and hypoplasia of the mandible, otic cup, and tympanic ring. Previously we showed that Galpha(q)/Galpha(11)-null mice die around E11.0, whereas Galpha(q)((-/-))Galpha(11)((+/-)) mice survive to birth with hypomorphic phenotypes similar to, but less severe than, ET(A) or ET-1-null mice. To determine whether ET-1 signaling is transduced by Galpha(q)/Galpha(11) proteins, we examined the expression patterns of several ET-1 dependent and independent transcription factors in Galpha(q)/Galpha(11)-deficient embryos. Expression of genes encoding the ET-1-dependent transcription factors Dlx3, Dlx6, dHAND, and eHAND was specifically downregulated in the pharyngeal arches of Galpha(q)/Galpha(11)-deficient mice. In contrast, pharyngeal arch expression of the homeobox gene Msx1, which is not regulated by ET-1 signaling, was maintained in these embryos. We conclude that the Galpha(q) and Galpha(11) proteins serve as the intracellular mediators of ET-1 signaling in the pharyngeal arch mesenchyme.

Animals↗

PubMed2002

Heart development: learning from mistakes.

Congenital heart disease in humans results from abnormal morphogenesis of the embryonic cardiovascular system. The characterization of mutations affecting cardiovascular development in animal models ranging from flies to mice has identified many of the key signaling molecules and transcriptional regulators of heart formation. Many of these molecules are also mutated in familial forms of human congenital heart disease. Through the use of animal models combined with analysis of human pedigrees, a molecular framework that controls formation of the vertebrate heart is beginning to emerge.

Animals↗

PubMed2002

Misexpression of dHAND induces ectopic digits in the developing limb bud in the absence of direct DNA binding.

Basic helix-loop-helix (bHLH) transcription factors control developmental decisions in a wide range of embryonic cell types. The HLH motif mediates homo- and heterodimerization, which juxtaposes the basic regions within the dimeric complex to form a bipartite DNA binding domain that recognizes a DNA consensus sequence known as an E-box. eHAND and dHAND (also known as HAND1 and HAND2) are closely related bHLH proteins that control cardiac, craniofacial and limb development. Within the developing limb, dHAND expression encompasses the zone of polarizing activity in the posterior region, where it has been shown to be necessary and sufficient to induce the expression of the morphogen sonic hedgehog. Misexpression of dHAND in the anterior compartment of the limb bud induces ectopic expression of sonic hedgehog, with resulting preaxial polydactyly and mirror image duplications of posterior digits. To investigate the potential transcriptional mechanisms involved in limb patterning by dHAND, we have performed a structure-function analysis of the protein in cultured cells and ectopically expressed dHAND mutant proteins in the developing limbs of transgenic mice. We show that an N-terminal transcriptional activation domain, and the bHLH region, are required for E-box-dependent transcription in vitro. Remarkably, however, digit duplication by dHAND requires neither the transcriptional activation domain nor the basic region, but only the HLH motif. eHAND has a similar limb patterning activity to dHAND in these misexpression experiments, indicating a conserved function of the HLH regions of these proteins. These findings suggest that dHAND may act via novel transcriptional mechanisms mediated by protein-protein interactions independent of direct DNA binding.

Amino Acid Sequence↗