A5088941103- Congenital heart defects research
- Craniofacial Disorders and Treatments
- Cleft Lip and Palate Research
- Developmental Biology and Gene Regulation
- dental development and anomalies
- Hedgehog Signaling Pathway Studies
- Congenital Ear and Nasal Anomalies
- Animal Genetics and Reproduction
- Congenital Heart Disease Studies
- MicroRNA in disease regulation
- Cancer-related molecular mechanisms research
- Cell Adhesion Molecules Research
- Tissue Engineering and Regenerative Medicine
- Nitric Oxide and Endothelin Effects
- Biomedical and Engineering Education
- Delphi Technique in Research
- Congenital Diaphragmatic Hernia Studies
- Genomic variations and chromosomal abnormalities
- Genetics and Neurodevelopmental Disorders
- CRISPR and Genetic Engineering
- Occupational and environmental lung diseases
- Tracheal and airway disorders
- Genomics and Rare Diseases
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Coronary Artery Anomalies
University of Colorado Anschutz Medical Campus
2016-2025
University of Colorado Denver
2006-2024
International Craniofacial Institute
2018
Florida Craniofacial Institute
2011
Baylor University
2007
University of Colorado Health
2006
University of Louisville
2003-2005
Howard Hughes Medical Institute
1992-2004
The University of Texas Southwestern Medical Center
1992-2004
University of Louisville Hospital
2003
ABSTRACT Neural crest cells arise in the dorsal aspect of neural tube and migrate extensively to differentiate into a variety non-neural tissues. While interactions between their local environments are required for proper development these tissues, little information is available about molecular nature cell-cell cephalic development. Here we demonstrate that mice deficient one type endothelin receptor, ETA, mimic human conditions collectively termed CATCH 22 or velocardiofacial syndrome,...
Recent gene targeting studies have revealed unexpected roles for endothelins in the development of neural crest-derived tissues. Endothelin converting enzyme-1 (ECE-1) catalyzes proteolytic activation big endothelin-1 to endothelin-1(ET-1) vitro. However, importance ECE-1 cleavage multiple endothelin pathways vivo is unknown. Here we generated a targeted null mutation mouse gene. ECE-1-/- term embryos exhibited craniofacial and cardiac abnormalities virtually identical defects seen ET-1 A...
Transgenic mice overexpressing a constitutively active human TGF-beta1 under control of the rat phosphoenolpyruvate carboxykinase regulatory sequences developed fibrosis liver, kidney, and adipose tissue, exhibited severe reduction in body fat. Expression transgene hepatocytes resulted increased collagen deposition, altered lobular organization, hepatocyte turnover, extreme cases, hemorrhage thrombosis. Renal expression was localized to proximal tubule epithelium, associated with...
The intercellular signaling mediated by endothelins and their G protein-coupled receptors has recently been shown to be essential for the normal embryonic development of subsets neural crest cell derivatives. Endothelin-1 (ET-1) is proteolytically generated from its inactive precursor endothelin-converting enzyme-1 (ECE-1) acts on endothelin-A (ETA) receptor. Genetic disruption this ET-1/ECE-1/ETA pathway results in defects branchial arch- derived craniofacial tissues, as well cardiac...
Kabuki syndrome (KS) is a rare multiple congenital anomaly characterized by distinctive facial features, global developmental delay, intellectual disability and cardiovascular musculoskeletal abnormalities. While mutations in KMT2D have been identified majority of KS patients, few patients KDM6A. We analyzed 40 individuals clinically diagnosed with for Mutations were detected 12 KDM6A 4 cases, respectively. Observed included single-nucleotide variations indels leading to frame shifts,...
Endothelin-converting enzyme-1 and -2 (ECE-1 -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects specific subsets of neural crest–derived tissues, including branchial arch–derived craniofacial structures, aortic arch arteries, cardiac outflow tract ECE-1 knockout mice. To examine role ECE-2 cardiovascular development, we have now generated a null mutation by...
Neural crest cells play a key role in craniofacial development. The endothelin family of secreted polypeptides regulates development several neural sublineages, including the branchial arch crest. basic helix–loop–helix transcription factor dHAND is also required for development, and endothelin-1 ( ET-1 ) mutant embryos, expression arches down-regulated, implicating it as transcriptional effector action. To determine mechanism that links signaling to transcription, we analyzed gene cis...
The lower jaw skeleton is derived from cephalic neural crest (CNC) cells that reside in the mandibular region of first pharyngeal arch. Endothelin-A receptor (Ednra) signaling crucial for their development, as Ednra(-/-) mice are born with severe craniofacial defects resulting neonatal lethality. In this study, we undertook a more detailed analysis arch development embryos to better understand cellular and molecular basis these defects. We show most structures undergo homeotic transformation...
The basic helix-loop-helix transcription factor dHAND is expressed in the mesenchyme of branchial arches and developing heart. Mice homozygous for a (Hand2) null mutation die early embryogenesis from cardiac abnormalities, precluding analysis potential role arch development. Two independent enhancers control expression heart arches. Endothelin-1 (ET-1) signaling regulates enhancer required To determine development to assess ET-1-dependent regulation vivo, we deleted this by homologous...
Lower jaw development is a complex process in which multiple signaling cascades establish proximal-distal organization. These are regulated both spatially and temporally constantly refined through induction of normal signals inhibition inappropriate signals. The connective tissue the tongue arises from cranial neural crest cell-derived ectomesenchyme within mandibular portion first pharyngeal arch likely to be impacted by this signaling. Although developmental mechanisms behind later aspects...
Development of vertebrate jaws involves patterning neural crest-derived mesenchyme cells into distinct subpopulations along the proximal-distal and oral-aboral axes. Although molecular mechanisms axis have been well studied, little is known regarding axis. Using unbiased single-cell RNA-seq analysis followed by in situ gene expression profiles, we show that Shh Bmp4 signaling pathways are activated a complementary pattern mouse embryonic mandibular arch. Tissue-specific inactivation hedgehog...
The cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene is expressed in multiple tissues and regulated a complex tissue-specific manner. To map the cis-acting DNA elements that direct this expression, we made transgenic mice containing truncated PEPCK-human growth hormone (hGH) fusion genes. transgenes contained PEPCK promoter fragments with 5' endpoints at -2088, -888, -600, -402, -207 bp, while 3' endpoint was +69 bp. Immunohistochemical analysis showed -2088 transgene correct cell...
Jaw morphogenesis is a complex event mediated by inductive signals that establish and maintain the distinct developmental domains required for formation of hinged jaws, defining feature gnathostomes. The mandibular portion pharyngeal arch one patterned dorsally JAGGED-NOTCH signaling ventrally Endothelin receptor-A (EDNRA) signaling. Loss EDNRA disrupts normal ventral gene expression, result which homeotic transformation mandible into maxilla-like structure. However, loss does not in...
Abstract The mesothelium lines body cavities and surrounds internal organs, widely contributing to homeostasis regeneration. Mesothelium disruptions cause visceral anomalies mesothelioma tumors. Nonetheless, the embryonic emergence of mesothelia remains incompletely understood. Here, we track mesothelial origins in lateral plate mesoderm (LPM) using zebrafish. Single-cell transcriptomics uncovers a post-gastrulation gene expression signature centered on hand2 distinct LPM progenitor cells....
ABSTRACT The Society for Craniofacial Genetics and Developmental Biology (SCGDB) hosted its 47th Annual Meeting on September 9–10, 2024, at the Stowers Institute Medical Research Children's Mercy in Kansas City, Missouri. On opening day, Drs. Jean‐Pierre Saint‐Jeannet Elizabeth Leslie received SCGDB Distinguished Scientist Awards recognition of their exceptional contributions to craniofacial biology. Additionally, Dr. Daniel Jensen discussed his unique perspective Treacher Collins syndrome,...
Vertebrate jaw development is coordinated by highly conserved ligand-receptor systems such as the peptide ligand Endothelin 1 (Edn1) and receptor type A (Ednra), which are required for patterning of lower structures. The Edn1/Ednra signaling pathway establishes identity progenitor cells regulating expression numerous genes, but intracellular mechanisms linking activation to gene regulation remain poorly understood. As a first step towards elucidating this mechanism, we examined function...
A putative adipocyte-specific enhancer has been mapped to approximately 1 kilobase pair upstream of the cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene. In present study, we used transgenic mice identify and characterize 413-base (bp) region between −1242 −828 bp as a <i>bona fide</i> <i>in vivo</i>. This functioned most efficiently in context PEPCK promoter. The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) 9-<i>cis</i>-retinoic acid (RXR) are required for...