A5002680652- Hedgehog Signaling Pathway Studies
- Lymphatic System and Diseases
- Genetic and Kidney Cyst Diseases
- Developmental Biology and Gene Regulation
- Cellular Mechanics and Interactions
- Epigenetics and DNA Methylation
- Angiogenesis and VEGF in Cancer
- Pluripotent Stem Cells Research
- Ion channel regulation and function
- Microtubule and mitosis dynamics
- Vascular Malformations and Hemangiomas
- Congenital heart defects research
- Muscle Physiology and Disorders
- Connective Tissue Growth Factor Research
- Biomarkers in Disease Mechanisms
- Lymphatic Disorders and Treatments
- Wnt/β-catenin signaling in development and cancer
- Molecular Biology Techniques and Applications
- Ion Transport and Channel Regulation
- Hippo pathway signaling and YAP/TAZ
- Connective tissue disorders research
- Biochemical Analysis and Sensing Techniques
- 3D Printing in Biomedical Research
- Planarian Biology and Electrostimulation
- Vestibular and auditory disorders
St. Jude Children's Research Hospital
2008-2025
Pediatrics and Genetics
2014
University of North Carolina at Chapel Hill
1991-1993
The origin of the mammalian lymphatic vasculature has been debated for more than 100 years. Whether endothelial cells have a single or dual, venous mesenchymal remains controversial. To resolve this debate, we performed Cre/loxP -based lineage-tracing studies using mouse strains expressing Cre recombinase under control Tie2 , Runx1 Prox1 promoter elements. These studies, together with analysis -mutant embryos lacking definitive hematopoiesis, conclusively determined that from venous-derived...
The activity of the homeobox gene Prox1 is necessary and sufficient for venous blood endothelial cells (BECs) to acquire a lymphatic cell (LEC) fate. We determined that differentiated LEC phenotype plastic, reprogrammable condition depends on constant its maintenance. show conditional down-regulation during embryonic, postnatal, or adult stages reprogram LECs into BECs. Consequently, identity mutant vessels also partially reprogrammed as they some features typical vasculature. siRNA-mediated...
During development, morphogens pattern tissues by instructing cell fate across long distances. Directly visualizing morphogen transport in situ has been inaccessible, so the molecular mechanisms ensuring successful delivery remain unclear. To tackle this longstanding problem, we developed a mouse model for compromised sonic hedgehog (SHH) and discovered that endocytic recycling promotes SHH loading into signaling filopodia called cytonemes. We optimized methods to preserve vivo cytonemes...
The mammalian lymphatic vasculature is important for returning fluids from the extracellular tissue milieu back to blood circulation. We showed previously that Prox1 dosage development of vasculature. lack activity results in complete absence endothelial cells (LECs). In heterozygous embryos, number LECs reduced because a decrease progenitor pool cardinal vein. This reduction caused by some being unable maintain expression. this study, we identified Vegfr3 , cognate receptor lymphangiogenic...
Prox1 heterozygous mice have a defective lymphatic vasculature and develop late-onset obesity. Chyle abnormally leaks from those vessels, accumulates in the surrounding tissues, causes an increase adipose tissue. We characterized lymphatics of Prox1+/- to determine whether extent obesity correlated with severity defects. The exhibited reduced tracer clearance ear skin, dysfunctional perfusion lower legs, uptake into deep collectors during mechanostimulation prior onset Ear vessels leg were...
Morphogens function in concentration-dependent manners to instruct cell fate during tissue patterning. The cytoneme morphogen transport model posits that specialized filopodia extend between morphogen-sending and responding cells ensure appropriate signaling thresholds are achieved. How morphogens transported along deployed from cytonemes, how quickly a cytoneme-delivered, receptor-dependent signal is initiated, whether these processes conserved across phyla not known. Herein, we reveal the...
Impaired cardiac muscle growth and aberrant myocyte arrangement underlie congenital heart disease cardiomyopathy. We show that cardiac-specific inactivation of the murine homeobox transcription factor Prox1 results in disruption expression localisation sarcomeric proteins, gross myofibril disarray growth-retarded hearts. Furthermore, we demonstrate is required for direct transcriptional regulation genes encoding structural proteins α-actinin, N-RAP zyxin, which collectively function to...
Background The homeobox gene Prox1 is required for lens, retina, pancreas, liver, and lymphatic vasculature development expressed in inner ear supporting cells neurons. Methodology/Principal Findings We have investigated the role of developing mouse taking advantage available standard conditional mutant strains using Tg(Pax2-Cre) Tg(Nes-Cre). A severe reduction size canal cristae but not other vestibular organs or cochlea was identified E18.5 Prox1Flox/Flox; ear. In these embryos, hair cell...
Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow retract with the cell cycle in response to extracellular cues. Disruption PC homeostasis corrupts regulation, placing significant pressure on pathway maintain ciliary fitness. Mechanisms by which robustness ensured SHH-stimulated cells not yet known. Herein, we reveal crosstalk circuit induced...
The lymphatic vasculature drains lymph fluid from the tissue spaces of most organs and returns it to blood for recirculation. Before reaching circulatory system, antigens pathogens transported by are trapped nodes. As proposed Florence Sabin more than a century ago recently validated, mammalian has venous origin is derived primitive sacs scattered along embryonic body axis. Also as Sabin, been generally accepted that nodes originate those sacs. However, we now demonstrate initiation node...
Abstract Sonic Hedgehog (SHH) signaling functions in temporal- and context-dependent manners to pattern diverse tissues during embryogenesis. The signal transducer Smoothened (SMO) is activated by sterols, oxysterols, arachidonic acid (AA) through binding pockets its extracellular cysteine-rich domain (CRD) 7-transmembrane (7TM) bundle. In vitro analyses suggest SMO allosterically enhanced combinatorial ligand these but vivo evidence of allostery lacking. Herein, we map an AA pocket at the...
The G protein-coupled receptor Smoothened (Smo) is the signal transducer of Sonic Hedgehog (Shh) pathway. Smo signals through protein-dependent and -independent routes, with protein-independent canonical signaling to Gli effectors requiring accumulation in primary cilium. mechanisms controlling activation trafficking are not yet clear but likely entail small-molecule binding pockets its extracellular cysteine-rich domain (CRD) and/or transmembrane bundle. Here, we demonstrate that cytosolic...
We have previously shown that monoclonal antibody E12 (MAb E12), one of several such antibodies raised against theophylline-treated Necturus gallbladder (NGB) epithelial cells, inhibits the chloride conductance in apical membrane tissue. Since channels are critical to secretory function epithelia many different animals, we used this determine whether conserved, and an immunoaffinity column isolate channel protein. now demonstrate MAb cross-reacts with detergent-solubilized extracts tissues...
Developmental tissue patterning and postdevelopmental homeostasis depend upon controlled delivery of cellular signals called morphogens. Morphogens act in a concentration- time-dependent manner to specify distinct transcriptional programs that instruct reinforce cell fate. One mechanism by which appropriate morphogen signaling thresholds are ensured is through the proteins specialized filopodia cytonemes. Cytonemes very thin (≤200 nm diameter) can grow lengths several hundred microns, makes...
Developmental tissue patterning and postdevelopmental homeostasis depend upon controlled delivery of cellular signals called morphogens. Morphogens act in a concentration- time-dependent manner to specify distinct transcriptional programs that instruct reinforce cell fate. One mechanism by which appropriate morphogen signaling thresholds are ensured is through the proteins specialized filopodia cytonemes. Cytonemes very thin (≤200 nm diameter) can grow lengths several hundred microns, makes...
We have purified a protein from Necturus maculosus gallbladder cells that forms chloride channels in an artificial membrane. The same apparently can form are highly selective for but conductances varying 9 to about 150 pS. high-conductance blocked by the monoclonal antibody used purify protein, this has no effect on 9-pS channels. observation gating of low- and states is independent affects only latter implications regarding control conductance cell membranes different types described those cells.
Summary Morphogens function in concentration-dependent manners to instruct cell fate during tissue patterning. Molecular mechanisms by which these signaling gradients are established and reinforced remain enigmatic. The cytoneme transport model posits that specialized filopodia extend between morphogen-sending responding cells ensure appropriate signal activation thresholds achieved across developing tissues. How morphogens transported along deployed from cytonemes is not known. Herein we...
Journal Article Integrative Microscopy Approaches Reveal Specialized Signaling Filopodia Promote Morphogen Gradient Formation during Mammalian Development Get access Eric T Hall, Hall Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States Search for other works by this author on: Oxford Academic Google Scholar Elizabeth R Cleverdon, Cleverdon Miriam E Dillard, Dillard Yan Zhang, Zhang Randall Wakefield, Wakefield Tissue Imaging Center,...
ABSTRACT Sonic Hedgehog (SHH) signaling is an essential driver of embryonic patterning that, when corrupted, leads to developmental disorders and cancers. SHH effector responses are organized through nonmotile primary cilia that grow retract with the cell cycle in response distinct extracellular cues. Destabilization cilium length corrupts pathway regulation, which places significant pressure on maintain ciliary architecture. Herein, we investigate whether promotes control. We reveal a...