A5003676417- Hedgehog Signaling Pathway Studies
- Developmental Biology and Gene Regulation
- Pluripotent Stem Cells Research
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Cleft Lip and Palate Research
- Congenital limb and hand anomalies
- Neurogenesis and neuroplasticity mechanisms
- Genetic and Kidney Cyst Diseases
- Congenital heart defects research
- Single-cell and spatial transcriptomics
- Gene Regulatory Network Analysis
- Congenital Ear and Nasal Anomalies
- Craniofacial Disorders and Treatments
- Chromatin Remodeling and Cancer
- Cancer Immunotherapy and Biomarkers
- Immune Response and Inflammation
- Neonatal Respiratory Health Research
- Urological Disorders and Treatments
- NF-κB Signaling Pathways
- Cancer Cells and Metastasis
- Cerebrospinal fluid and hydrocephalus
- Mast cells and histamine
- Axon Guidance and Neuronal Signaling
- Biomedical Research and Pathophysiology
Imperial College London
2020-2024
The Francis Crick Institute
2015-2022
The University of Queensland
2008-2017
Research Institute for Bioscience and Biotechnology
2013
Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of body. The prevailing view is neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility define how adopt region-specific fates. Together genetic and biochemical perturbations, identified developmental time window which genome-wide chromatin-remodeling events...
ABSTRACT During development, gene regulatory networks allocate cell fates by partitioning tissues into spatially organised domains of expression. How the sharp boundaries that delineate these expression patterns arise, despite stochasticity associated with regulation, is poorly understood. We show, in vertebrate neural tube, using perturbations coding and regions, structure network contributes to boundary precision. This achieved, not reducing noise individual genes, but configuration...
Abstract WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. Here we provide evidence that these distinct functions are conducted by transcription factor SOX2, which adopts different modes chromatin interaction regulatory element selection depending on its level expression. At high levels, SOX2 displaces nucleosomes from elements with high-affinity binding sites, recruiting effector...
Fibroblast growth factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of genes unclear. Moreover, for differentiation progress, FGF signalling must decline. Why these dynamics are required has not been determined. Here, we show that dephosphorylation effector kinase ERK1/2 rapidly increases accessibility at mouse and, using ATAC-seq human embryonic stem cell derived spinal cord precursors, demonstrate this...
The vertebrate hedgehog receptor patched 1 (Ptc1) is crucial for negative regulation of the sonic (Shh) pathway during anterior-posterior patterning limb. We have conditionally inactivated Ptc1 in mesenchyme mouse limb using Prx1-Cre. This results constitutive activation (Hh) signalling early stages budding. Our data suggest that variations timing and efficiency Cre-mediated excision result differential forelimb hindlimb phenotypes. Hindlimbs display polydactyly (gain digits) a molecular...
Defects such as cleft lip with or without palate (CL/P) are among the most common craniofacial birth defects in humans. In many cases, underlying molecular and cellular mechanisms that result these debilitating anomalies remain largely unknown. Perturbed hedgehog (HH) signalling plays a major role development, mutations number of pathway constituents underlie disease. particular, gene encoding HH receptor negative regulator, patched1 (PTCH1), associated both sporadic familial forms clefting,...
The bones of the vertebrate limb form by process endochondral ossification, whereby mesenchyme condenses to an intermediate cartilage scaffold that is then replaced bone. Although Indian hedgehog (IHH) known control hypertophic differentiation chondrocytes during this process, role signaling in earlier stages chondrogenesis less clear. We have conditionally inactivated receptor Ptc1 undifferentiated mouse using Prx1-Cre, thus inducing constitutively active ligand-independent signaling. In...
Abstract The NET/Nlz family of zinc finger transcription factors contribute to aspects developmental growth and patterning across evolutionarily diverse species. To date, however, these molecules remain largely uncharacterized in mouse chick. We previously reported that limb bud expression Zfp503 , the orthologue zebrafish nlz2 / znf503 is dependent on Gli3. Here, we show Znf503 expressed a restricted pattern during chick embryogenesis, with particularly dynamic developing limbs, face,...
Abstract WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. We provide evidence that these distinct functions are conducted by transcription factor SOX2, which adopts different modes chromatin interaction regulatory element selection depending on its level expression. At high levels, SOX2 acts as a pioneer factor, displacing nucleosomes from elements with affinity binding sites...
During development, cells express precise gene expression programmes to assemble the trunk of body plan. Appropriate control over duration transcription factor Cdx2 is critical achieve this outcome, yet, how onset, maintenance or termination , has remained unclear. Here, we delineate cis-regulatory logic orchestrating dynamic in mouse caudal epiblast progenitors and their derivatives - spinal cord presomitic mesoderm. Combining CRISPR-mediated deletion regulatory elements with vitro models...
Abstract Pitrm1 is a zinc metalloendopeptidase that has been implicated in Alzheimer's disease and mitochondrial peptide degradation, but to date no major role embryonic development documented. In screen for genes regulated by hedgehog signaling the mouse limb, we showed expression of upregulated response loss Gli3 transcription factor. Here confirm spatial changes mutant limb examine Shh null Ptch1 conditional deletion mutants. wild‐type mice, expressed number developing tissues known be...
Abstract Fibroblast Growth Factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of genes unclear. Moreover, for differentiation progress FGF signalling has decline. Why this dynamic required not been determined. Here we show that dephosphorylation effector kinase ERK1/2 rapidly increases accessibility at mouse embryos and, using ATAC-seq human embryonic stem cell derived spinal cord precursors, demonstrate...
Abstract During development, gene regulatory networks allocate cell fates by partitioning tissues into spatially organised domains of expression. How the sharp boundaries that delineate these expression patterns arise, despite stochasticity associated with regulation, is poorly understood. We show, in vertebrate neural tube, using perturbations coding and regions, structure network contributes to boundary precision. This achieved, not reducing noise individual genes, but configuration...
The central nervous system contains a vast array of cell types that are produced along the length rostrocaudal axis. This diversity in identity is established during embryonic development, and ensures physiologically distinct develop appropriate position body. Understanding how this cellular arises remains major challenge to field developmental biology. In more recent years, approaches using pluripotent stem cells (ESCs) as vitro models development have revealed many insights into...
Summary Neural induction in vertebrates generates a central nervous system that extends the rostral-caudal length of body. The prevailing view is neural cells are initially induced with anterior (forebrain) identity, caudalising signals then converting proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility assays define how adopt region-specific fates. Together genetic and biochemical perturbations identified developmental time window which...