A5005227452- Developmental Biology and Gene Regulation
- Animal Genetics and Reproduction
- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- Cancer, Hypoxia, and Metabolism
- RNA modifications and cancer
- Wnt/β-catenin signaling in development and cancer
- Congenital heart defects research
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Cystic Fibrosis Research Advances
- Colorectal Cancer Treatments and Studies
- Hedgehog Signaling Pathway Studies
- Energy Harvesting in Wireless Networks
- Ubiquitin and proteasome pathways
- Genomic variations and chromosomal abnormalities
- Biochemical and Molecular Research
- Reproductive System and Pregnancy
- Molecular Biology Techniques and Applications
- Genetic Neurodegenerative Diseases
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Nuclear Structure and Function
- Protein Degradation and Inhibitors
- Connective tissue disorders research
- Congenital Diaphragmatic Hernia Studies
Case Western Reserve University
2014-2024
Target (United States)
2020-2024
University School
2004-2024
University of Lisbon
2023
Royal College of Surgeons in Ireland
2018
University of Oklahoma
2005
University of Canterbury
2005
National University of Ireland
2005
University Hospitals of Cleveland
1999-2004
Jackson Laboratory
2004
ABSTRACT Members of the Notch family transmembrane receptors mediate a number developmental decisions in invertebrates. In order to study function vertebrate organism, we have mutated Notch1 gene mouse. is required for embryonic survival second half gestation. first gestation, found no effect mutation on normal programs neurogenesis, myogenesis or apoptosis. We conclude that not essential these processes, at least early postimplantation development. However, somitogenesis delayed and...
ABSTRACT We have used RT-PCR to screen pluripotent murine embryonic stem cells identify receptor tyrosine kinases (RTKs) potentially involved in the determination or differentiation of cell lineages during early mouse development. Fourteen different kinase sequences were identified. The expression patterns four RTKs been examined and all are expressed embryo during, shortly after, gastrulation. report here detailed pattern one such RTK, flt-related gene flk-1. In situ hybridization analysis...
Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains maintained throughout the lifespan. The mechanisms of their generation maintenance largely unknown. Here, we show that neural cells independent RBP-J κ, a key molecule Notch signaling, by using κ −/− an cell-derived neurosphere assay. However, pathway molecules essential for cells; they depleted or Notch1 mice. also deficient presenilin1 ( PS1 ) gene, regulator reduced +/− adult...
ABSTRACT The Notch pathway functions in multiple cell fate determination processes invertebrate embryos, including the decision between neuroblast and epidermoblast lineages Drosophila. In mouse, targeted mutation of genes Notch1 RBP-Jk has demonstrated a role for these somite segmentation, but function neurogenesis decisions not been shown. Here we show that mutations lead to altered expression signalling homologues Hes-5, Mash-1 Dll1, resulting enhanced neurogenesis. Precocious neuronal...
ABSTRACT Exogenous retinoic acid (RA) has teratogenic effects on vertebrate embryos and alters Hox-C gene expression in vivo vitro. We wish to examine whether RA a role the normal regulation of genes, altered response leads abnormal morphology. The 3′ Hox-2 genes (Hox-2.9, Hox-2.8, Hox-2.6 Hox-2.1) 5′ (Hox-2.5) were examined by whole-mount situ hybridization 4 hours after mater-nal administration doses embry-onic day 7 9. was found be ectopically induced anterior regions stage-specific...
Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making more dependent on glutamine. Compared with isogenic wild-type (WT) mutant CRCs convert substantially to α-ketoglutarate replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an...
In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of in cells, yielding responses. Intravenously administered gene-editing LNPs activatable tdTomato mice achieved >70% lung editing, sustaining expression >80% epithelial cells 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X...
Neutrophil Extracellular Traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens causes tissue damage in diseases. Whether NETs can cancer cells is unexplored. Here, we report that combination glutaminase inhibitor CB-839 5-FU inhibits the growth PIK3CA mutant colorectal cancers (CRCs) xenograft, syngeneic, genetically engineered mouse models part through NETs. Disruption by either DNase I treatment or depletion neutrophils CRCs...
Otx2, a mouse homolog of the Drosophila orthodenticle gene, is first widely expressed in epiblast but becomes progressively restricted to anterior third embryo by headfold stage. This progressive restriction correlates with migration mesoderm embryo, suggesting that interactions may be involved setting up domain Otx2 expression vivo. Using explant-recombination assays, we have obtained evidence positive signal from mesendoderm required stabilize vivo, whereas negative later-forming posterior...
Cajal bodies (CBs) are nuclear suborganelles involved in the biogenesis of small ribonucleoproteins (snRNPs). In addition to snRNPs, they highly enriched basal transcription and cell cycle factors, nucleolar proteins fibrillarin (Fb) Nopp140 (Nopp), survival motor neuron (SMN) protein complex, CB marker protein, p80 coilin. We report generation knockout mice lacking COOH-terminal 487 amino acids Northern Western blot analyses demonstrate that we have successfully removed full-length coilin...
A loss-of-function mutation in the mouse delta-like3 (Dll3) gene has been generated following targeting, and results severe axial skeletal defects. These defects, which consist of highly disorganised vertebrae costal are similar to those associated with Dll3-dependent pudgy mutant spondylocostal dysplasia (MIM 277300) humans. This study demonstrates that Dll3neo Dll3pu functionally equivalent alleles respect dysplasia, we suggest three human DLL3 mutations also null allele. Our phenotypic...
Cited2 is a cAMP-responsive element-binding protein (CBP)/p300 interacting transcriptional modulator and proposed negative regulator for hypoxia-inducible factor (HIF)-1α through its competitive binding with HIF-1α to CBP/p300. Disruption of the gene encoding embryonic lethal because defects in development heart neural tube. Morphological Doppler echocardiographic analyses −/− embryos reveal severe cardiovascular abnormalities, including pulmonic arterial stenosis ventricular septal...
The N-myc proto-oncogene encodes a putative transcription factor that has been postulated to be involved in the control of differentiation number lineages at various stages during mammalian embryogenesis. We have generated leaky mutation by gene targeting embryonic stem cells. In this allele, neo(r) was inserted into first intron N-myc, such way alternative splicing around insertion could result generation normal transcript addition mutant transcript. Mice homozygous for died immediately...
Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in huntingtin protein. Full-length thought to be a predominant HEAT repeat α-solenoid, implying role as facilitator macromolecular complexes. Here we have investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex 2 (PRC2), suggested shared embryonic deficiency phenotypes. Analysis set full-length recombinant huntingtins, different regions,...
Abstract PIK3CA encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including ∼30% colorectal cancer. Oncogenic mutations render cancers more dependent on glutamine. Here we report that glutaminase inhibitor CB-839 preferentially inhibits xenograft growth PIK3CA-mutant, but not wild-type (WT), cancers. Moreover, combination 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression models. treatment increased reactive oxygen species caused nuclear...
Clinical expression of Hirschsprung disease (HSCR) requires the interaction multiple susceptibility genes. Molecular genetic analyses have revealed that interactions between mutations in genes encoding RET receptor tyrosine kinase and endothelin type B (EDNRB) are central to genesis HSCR. We established two locus noncomplementation assays mice, using allelic series at Ednrb context Ret kinase-null heterozygotes, understand clinical presentation, incomplete penetrance, variation length...