A5051919465- Retinal Development and Disorders
- Single-cell and spatial transcriptomics
- Zebrafish Biomedical Research Applications
- RNA Research and Splicing
- Cell Image Analysis Techniques
- Developmental Biology and Gene Regulation
- RNA modifications and cancer
- Hippo pathway signaling and YAP/TAZ
- Neurogenesis and neuroplasticity mechanisms
- CRISPR and Genetic Engineering
- Cancer-related molecular mechanisms research
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA regulation and disease
- Cellular transport and secretion
- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- Advanced Biosensing Techniques and Applications
- Retinal Diseases and Treatments
- Fish biology, ecology, and behavior
- Genomics and Chromatin Dynamics
- Connexins and lens biology
- Hedgehog Signaling Pathway Studies
- Viral Infectious Diseases and Gene Expression in Insects
- Molecular Biology Techniques and Applications
- Iron-based superconductors research
Washington University in St. Louis
2011-2024
St. Jude Children's Research Hospital
2024
University of Alabama at Birmingham Hospital
2023
Medical College of Wisconsin
2009-2021
Brotman Baty Institute
2021
Schlumberger (British Virgin Islands)
1988-2020
Johns Hopkins Medicine
2014-2019
Johns Hopkins University
2014-2019
H. L. Snyder Medical Foundation
2017-2018
Northwestern University
2006-2017
The identification of ultraconserved noncoding sequences in vertebrates has been associated with developmental regulators and DNA-binding proteins. One the first these was identified intergenic region between Dlx-5 Dlx-6 genes, members Dlx/ dll homeodomain-containing protein family. In previous experiments, we showed that Sonic hedgehog treatment forebrain neural explants results activation Dlx-2 novel RNA (ncRNA), Evf-1 . this report, show Dlx-5/6 is transcribed to generate an alternatively...
Analysis of gene expression in single cells allows for decomposition cellular states as low-dimensional latent spaces. However, the interpretation and validation these spaces remains a challenge. Here, we present scCoGAPS, which defines from source single-cell RNA-sequencing (scRNA-seq) dataset, projectR, evaluates independent target datasets via transfer learning. Application developing mouse retina to scRNA-Seq reveals intrinsic relationships across biological contexts assays while...
The optic vesicle comprises a pool of bi-potential progenitor cells from which the retinal pigment epithelium (RPE) and neural retina fates segregate during ocular morphogenesis. Several transcription factors signaling pathways have been shown to be important for RPE maintenance differentiation, but an understanding initial fate specification determination this cell type is lacking. We show that Yap/Taz-Tead activity necessary sufficient progenitors adopt identity in zebrafish. A...
Elevated levels of low-density lipoprotein cholesterol (LDL-C) in plasma are a major contributor to cardiovascular disease, which is the leading cause death worldwide. Genome-wide association studies (GWAS) have identified 95 loci that associate with control lipid/cholesterol metabolism. Although GWAS results highly provocative, direct analyses contribution specific allelic variations regulating LDL-C has been challenging due difficulty accessing appropriate cells from affected patients. The...
Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis cell-fate specification in the developing central nervous system. In this study, we use integrated single-cell RNA ATAC sequencing (scATAC-seq) analysis mouse human retina to identify multiple interconnected, evolutionarily conserved GRNs composed cell-type-specific that both activate genes within own network inhibit other networks. These temporal patterning primary progenitors,...
Transcription-regulating long non-coding RNAs (lncRNAs) have the potential to control site-specific gene expression of thousands targets. Previously, we showed that Evf2, first described ultraconserved lncRNA, increases association transcriptional activators (DLX homeodomain proteins) key DNA enhancers, but represses expression. In this report, mass spectrometry shows Evf2/DLX1 ribonucleoprotein (RNP) contains SWI/SNF related chromatin-remodelers, Brahma 1 (BRG1, SMARCA4) and...
Abstract Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders. These genes produce alternative mRNA isoforms which remain poorly characterized, impeding understanding of how disease-associated mutations cause pathology. Here we introduce a strategy to define complete portfolios full-length encoded by individual genes. Applying this approach neural molecules, identify thousands unannotated expressed retina brain. By mass...
Müller glia (MG) are the only glial cell type produced by neuroepithelial progenitor cells that generate vertebrate retina. MG required to maintain retinal homeostasis and support survival of neurons. Furthermore, in certain classes, function as adult stem cells, mediating regeneration response injury. However, mechanisms regulate development poorly understood because there is considerable overlap gene expression between differentiated MG. We show LIM homeodomain transcription factor Lhx2...
Abstract Public archives of next-generation sequencing data are growing exponentially, but the difficulty marshaling this has led to its underutilization by scientists. Here, we present ASCOT, a resource that uses annotation-free methods rapidly analyze and visualize splice variants across tens thousands bulk single-cell sets in public archive. To demonstrate utility identify novel cell type-specific alternative exons nervous system leverage ENCODE GTEx study unique splicing photoreceptors....
Retinal ganglion cells (RGCs) relay visual information from the eye to brain. RGCs are first cell type generated during retinal neurogenesis. Loss of function transcription factor Atoh7, expressed in multipotent early neurogenic progenitors leads a selective and essentially complete loss RGCs. Therefore, Atoh7 is considered essential for conferring competence on generate Despite importance RGC specification, we find that inhibiting apoptosis Atoh7-deficient mice by Bax only modestly reduces...
Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse homeostasis, aging, diabetes, dry eye disease (DED), where tear deficiency predisposes cornea to recurrent In capture transcriptional states that accomplish continuous tissue turnover. We leverage our dataset...
Abstract The Rab family of small GTPases function as molecular switches regulating membrane and protein trafficking. Individual isoforms define are required for specific endosomal compartments. To facilitate in vivo investigation proteins, endosome biology general, we have generated transgenic zebrafish lines to mark manipulate proteins. We also developed software track quantify dynamics within time‐lapse movies. established ubiquitously express EGFP fusions Rab5c (early endosomes), Rab11a...
To gain insights into the cellular mechanisms of neurogenesis, we analyzed retinal neuroepithelia deficient for Llgl1, a protein implicated in apicobasal cell polarity, asymmetric division, shape and cycle exit. We found that vertebrate Llgl1 retained overt but had expanded apical domains. progenitors also increased Notch activity reduced rates neurogenesis. Blocking function by depleting Rbpj restored normal Experimental expansion domain, through inhibition Shroom3, Significantly, wild-type...
Abstract Age‐related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of on homeostasis, we used short‐lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) hallmarks loss. Bulk single‐cell RNA‐sequencing (scRNAseq) three age groups (6‐, 12‐, 18‐week‐old) identified transcriptional fingerprints killifish retina, unveiling pathways also...
ABSTRACT Retinal cell fate specification from multipotent retinal progenitors is governed by dynamic changes in chromatin structure and gene expression. Methylation at cytosines DNA (5mC) actively regulated for proper control of expression architecture. Numerous genes display active demethylation across development; a process that requires oxidation 5mC to 5-hydroxymethylcytosine (5hmC) controlled the ten-eleven translocation methylcytosine dioxygenase (TET) enzymes. Using an allelic series...
Abstract Müller glia (MG) are the principal glial cell type in vertebrate retina. Recent work has identified LIM homeodomain factor encoding gene Lhx2 as necessary for both Notch signaling and MG differentiation late-stage retinal progenitor cells (RPCs). However, extent to which interacts with other intrinsic regulators of is unclear. We investigated this question by investigating effects overexpression multiple transcriptional that either known or hypothesized control formation, wildtype...
Abstract Neural progenitor cells undergo identity transitions during development to ensure the generation different types of neurons and glia in correct sequence proportions. A number temporal factors that control these competence have been identified, but molecular mechanisms underlying their function remain unclear. Here, we asked how Casz1 , mammalian orthologue Drosophila castor regulates retinal development. We show is required transition between neurogenesis gliogenesis. Using BioID...