A5021391935- Epigenetics and DNA Methylation
- Pluripotent Stem Cells Research
- Pancreatic function and diabetes
- Renal and related cancers
- Genetic Syndromes and Imprinting
- Congenital heart defects research
- Prenatal Screening and Diagnostics
- Liver physiology and pathology
- Animal Genetics and Reproduction
- Molecular Biology Techniques and Applications
- Reproductive Biology and Fertility
- RNA Research and Splicing
- Genetic and Kidney Cyst Diseases
- Tissue Engineering and Regenerative Medicine
- Hedgehog Signaling Pathway Studies
- MicroRNA in disease regulation
- Morphological variations and asymmetry
- Genomics and Chromatin Dynamics
- TGF-β signaling in diseases
- Cancer-related molecular mechanisms research
- Cancer-related gene regulation
- Genetics and Neurodevelopmental Disorders
- Wnt/β-catenin signaling in development and cancer
- Fibroblast Growth Factor Research
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Amherst College
2011-2024
University of Massachusetts Amherst
2012-2024
Université Laval
2019
University of Pennsylvania
1995-2006
Fox Chase Cancer Center
2005
Harvard University
2000-2001
Howard Hughes Medical Institute
1997-2000
The H19 gene is imprinted with preferential expression from the maternal allele. putative imprinting control region for this locus hypermethylated on repressed paternal Although maternal-specific of observed in mouse blastocysts that develop vivo, biallelic has been documented embryos and embryonic stem cells experimentally manipulated by vitro culture conditions. In study effect methylation was determined. After 2-cell to blastocyst stage Whitten's medium, normally silent allele aberrantly...
The Smad proteins are important intracellular mediators of the transforming growth factor beta (TGFbeta) family secreted factors. Smad1 is an effector signals provided by bone morphogenetic protein (BMP) sub-group TGFbeta molecules. To understand role in mouse development, we have generated a loss-of-function allele using homologous recombination ES cells. Smad1-/- embryos die 10.5 dpc because they fail to connect placenta. Mutant first recognizable 7.0 dpc, owing characteristic localized...
The imprinted mouse H19 gene is hypermethylated on the inactive paternal allele in somatic tissues and sperm. Previous observations from a limited analysis have suggested that methylation of few CpG dinucleotides region upstream start transcription may be mark confers parental identity to alleles. Here we exploit bisulfite mutagenesis coupled with genomic sequencing derive status 68 CpGs reside 4-kb 5' transcription. This method reveals 2-kb positioned between 2 4 kb strikingly...
ABSTRACT TGFβ growth factors specify cell fate and establish the body plan during early vertebrate development. Diverse cellular responses are elicited via interactions with specific surface receptor kinases that in turn activate Smad effector proteins. Smad2-dependent signals arising extraembryonic tissues of mouse embryos serve to restrict site primitive streak formation anteroposterior identity epiblast. Here we have generated chimeric using lacZ-marked Smad2-deficient ES cells. Smad2...
Long noncoding RNAs (lncRNAs) exhibit diverse functions, including regulation of development. Here, we combine genome-wide mapping SMAD3 occupancy with expression analysis to identify lncRNAs induced by activin signaling during endoderm differentiation human embryonic stem cells (hESCs). We find that DIGIT is divergent Goosecoid (GSC) and expressed differentiation. Deletion the SMAD3-occupied enhancer proximal inhibits GSC definitive Disruption gene encoding depletion transcript reveal...
Fluorescent proteins have revolutionized modern biology with their ability to report the presence of tagged in living systems. Although several fluorescent been described which excitation and emission properties can be modulated by external triggers, no that activated from a silent dark state bright directly activity an enzyme. We developed version GFP fluorescence is completely quenched appendage hydrophobic quenching peptide tetramerizes prevents maturation chromophore. The fully restored...
The definitive endoderm arises as a naive epithelial sheet that produces the entire gut tube and associated organs including liver, pancreas lungs. Murine explant studies demonstrate fibroblast growth factor (FGF) signaling from adjacent tissues is required to induce hepatic gene expression isolated foregut endoderm. requirement of FGF during liver development examined by means small molecule inhibition whole embryo culture.Loss before induction results in morphological defects changes are...
Abstract With readily available transcriptome-wide data, understanding the role of each expressed gene is an essential next step. Although RNAi technologies allow for genome-wide screens in cell culture, these approaches cannot replace strategies discovery embryo. Here we present, first time, a knockdown screen mouse preimplantation embryos. Early mammalian development encompasses dynamic cellular, molecular and epigenetic events that are largely conserved from to man. We assayed 712 genes...
Mitochondria are essential for energy production and although they have their own genome, many nuclear-encoded mitochondrial ribosomal proteins (MRPs) required proper function of the organelle. Although mutations in MRPs been associated with human diseases, little is known about role during development. Presented here null phenotypes 21 in-depth characterization mouse embryos mutant Mrp genes Mrpl3, Mrpl22, Mrpl44, Mrps18c Mrps22 Loss each MRP results successful implantation egg-cylinder...
The primary cilium is a sensory organelle, defects in which cause wide range of human diseases including retinal degeneration, polycystic kidney disease and birth defects. functions cilia require specific receptors to be targeted the ciliary subdomain plasma membrane. Arf4 has been proposed sort cargo destined for at Golgi complex deemed key regulator protein trafficking. In this work, we show that binds targeting sequence (CTS) fibrocystin. Knockdown indicates it not absolutely required...
The multifaceted polycomb group gene Yin-Yang1 (Yy1) has been implicated in a variety of transcriptional regulatory roles both as an activator and silencer expression. Here we examine the role Yy1 during oocyte growth by conditional deletion locus growing oocyte. Our results indicate that YY1 is required for maturation granulosa cell expansion. In mutant oocytes, observe severely reduced expression Gdf9 Bmp15, suggesting mechanism underlying failure Consequently, infertility, estrus cycling,...
The definitive endoderm is the embryonic germ layer that gives rise to budding endodermal organs including thyroid, lung, liver and pancreas as well remainder of gut tube. DiI fate mapping whole embryo culture were used determine origin 9.5 days post coitum (dpc) dorsal ventral buds. Our results demonstrate progenitors each bud occupy distinct territories. Dorsal are located in medial overlying somites 2–4 between 2 11 somite stage (SS). forming found regions. One territory originates from...
Appropriate epigenetic regulation of gene expression during lineage allocation and tissue differentiation is required for normal development. One example genomic imprinting, which defined as parent-of-origin mono-allelic expression. Imprinting established largely due to differences arriving in the zygote from sperm egg haploid genomes. In mouse, there are approximately 150 known imprinted genes, many occur clusters that regulated together. cluster includes maternally expressed Igf2r,...
Microspherule protein 1 (MCRS1, also known as MSP58) is an evolutionarily conserved that has been implicated in various biological processes. Although a variety of functions have attributed to MCRS1 vitro , mammalian not studied vivo . Here we report essential during early murine development. Mcrs1 mutant embryos exhibit normal morphology at the blastocyst stage but cannot be recovered gastrulation, suggesting implantation failure. Outgrowth (OG) assays reveal blastocysts do form typical...
Mouse embryos lacking the polycomb group gene member Yin-Yang1 (YY1) die during peri-implantation stage. To assess post-gastrulation role of YY1, a conditional knock-out (cKO) strategy was used to delete YY1 from visceral endoderm yolk sac and definitive embryo. cKO display profound defects at 9.5 days post coitum (dpc), including disrupted angiogenesis in mesoderm derivatives altered epithelial characteristics endoderm. Significant changes both cell death proliferation were confined...
During development, the endoderm initiates organ‐restricted gene expression patterns in a spatiotemporally controlled manner. This process, termed induction, requires signals from adjacent mesodermal derivatives. Fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) emanating cardiac mesoderm septum transversum mesenchyme (STM), respectively, are believed to be simultaneously uniformly required directly induce hepatic murine endoderm. Using small molecule inhibitors of BMP...
Mediator is an evolutionarily conserved multi-subunit complex, bridging transcriptional activators and repressors to the general RNA polymerase II (Pol II) initiation machinery. Though complex crucial for transcription of almost all Pol promoters in eukaryotic organisms, phenotypes individual subunit mutants are each distinct. Here, we report first time, essential role MED20 early mammalian embryo development. Although Med20 mutant mouse embryos exhibit normal morphology at E3.5 blastocyst...