A5004090996- Genetics and Neurodevelopmental Disorders
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Neurogenesis and neuroplasticity mechanisms
- Congenital heart defects research
- Pluripotent Stem Cells Research
- Neuroscience and Neuropharmacology Research
- Functional Brain Connectivity Studies
- Amyotrophic Lateral Sclerosis Research
- Pancreatic function and diabetes
- Developmental Biology and Gene Regulation
- Neurogenetic and Muscular Disorders Research
- Zebrafish Biomedical Research Applications
- Neuroinflammation and Neurodegeneration Mechanisms
- Genetic Neurodegenerative Diseases
- Microtubule and mitosis dynamics
- Alzheimer's disease research and treatments
- Autophagy in Disease and Therapy
- Neuroscience and Neural Engineering
- Cancer-related gene regulation
- Genetic Syndromes and Imprinting
- RNA modifications and cancer
- Chromatin Remodeling and Cancer
University College London
2018-2025
UK Dementia Research Institute
2018-2025
National Hospital for Neurology and Neurosurgery
2018-2025
Institute for Stem Cell Biology and Regenerative Medicine
2019-2024
Tata Institute of Fundamental Research
2011-2023
National Centre for Cell Science
2007-2011
Abstract The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G 4 C 2 repeat expansion in C9orf72 . repeats undergo bidirectional transcription to produce sense antisense RNA species, which are translated into dipeptide proteins (DPRs). As toxicity has been associated with both repeat-derived DPRs, targeting strands may provide the effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing...
The sequential production of neurons and astrocytes from neuroepithelial precursors is a fundamental feature central nervous system development. We report that LIM-homeodomain (LIM-HD) transcription factor Lhx2 regulates this transition in the developing hippocampus. Disrupting function embryonic hippocampus by utero electroporation organotypic slice culture caused premature at stages when are normally generated. therefore necessary to suppress astrogliogenesis during neurogenic period....
In the developing cerebral cortex, sequential transcriptional programs take neuroepithelial cells from proliferating progenitors to differentiated neurons with unique molecular identities. The regulatory changes that occur in chromatin of are not well understood. During deep layer neurogenesis, we show transcription factor LHX2 binds distal elements Fezf2 and Sox11 , critical determinants neuron subtype identity mouse neocortex. We demonstrate nucleosome remodeling histone deacetylase...
Significance The somatosensory barrels are a unique feature of the rodent cortex. Each barrel represents functional unit in which clustered innervation from an individual whisker connects with ring cortical neurons. This study reports that when single transcription factor, LIM homeobox 2, is deleted specifically cortex, neither cores nor walls able to form, although rudimentary mapping does occur. Understanding how form will shed light on neurocircuitry assembled its final stages, and this...
Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia and lead to lysosomal storage pathology neurons. We here report that physiological levels of mutant causes reduced numbers significantly impaired trafficking endolysosomes within neuronal dendrites, accompanied by increased dendritic branching. Mechanistically, this is due stable incorporation onto endolysosomes, which we show renders them unable traffic dendrites. This defect inability recruit ATPase VPS4,...
Insulin is the key regulator of glucose homeostasis in mammals, and glucose-stimulated insulin biosynthesis essential for maintaining levels a narrow range mammals. Glucose specifically promotes translation pancreatic β-islet, untranslated regions mRNA play role such regulation. Specific factors β-islets bind to 5' UTR regulate its translation. In present study we identify protein-disulfide isomerase (PDI) as biosynthesis. We show that both vitro vivo PDI can associate with mRNA....
Regulation of the neuron–glia cell-fate switch is a critical step in development CNS. Previously, we demonstrated that Lhx2 necessary and sufficient regulator this process mouse hippocampal primordium, such overexpression promotes neurogenesis suppresses gliogenesis, whereas loss has opposite effect. We tested series transcription factors for their ability to mimic suppress baseline also compensate resulting enhanced level gliogenesis hippocampus. Here, demonstrate novel function...
In the mammalian cerebral cortex, hippocampal primordium (Hcp) occupies a discrete position in dorsal telencephalic neuroepithelium adjacent to neocortical (Ncp). We examined transcriptomic and chromatin-level features that distinguish Hcp from Ncp mouse during early neurogenic period, embryonic day (E)12.5. ATAC-seq revealed was more accessible than at this stage. Motif analysis of differentially loci these tissues LHX2 as candidate transcription factor for modulating gene regulatory...
Glucose induced translation of insulin in pancreatic beta cells is mediated by the 5′UTR mRNA. We determined minimal sequence/structure rat gene1 for this regulation. show that specific factors islets bind to mRNA upon glucose stimulation. identified a 29‐nucleotide element sufficient form complex, and confer activation. Conserved residues predicted stem loop region un‐translated (UTR) seem be important complex formation
Insulin is a secreted peptide that controls glucose homeostasis in mammals, and insulin biosynthesis regulated by at many levels. Rodent encoded two non‐allelic genes. We have identified novel splice variant of the insulin2 gene mice constitutes about 75% total mRNA. The alternate splicing does not alter ORF but reduces 5′UTR 12 bases. A reporter containing short 5′UTR, more efficiently expressed cells, suggesting alternative mRNA could result an additional level regulation biosynthesis.
Protein cofactor Ldb1 regulates cell fate specification by interacting with LIM-homeodomain (LIM-HD) proteins in a tetrameric complex consisting of an LDB:LDB dimer that bridges two LIM-HD molecules, mechanism first demonstrated the Drosophila wing disc. Here, we demonstrate conservation this interaction regulation mammalian hippocampal development, which is profoundly defective upon loss either Lhx2 or Ldb1. Electroporation chimeric construct encodes Lhx2-HD and Ldb1-DD (dimerization...
Abstract Protein cofactor Ldb1 regulates cell fate specification by interacting with LIM-homeodomain (LIM-HD) proteins in a tetrameric complex consisting of an LDB:LDB dimer that bridges two LIM-HD molecules, mechanism first demonstrated the Drosophila wing disc. Here, we demonstrate conservation this interaction regulation mammalian hippocampal development, which is profoundly defective upon loss either Lhx2 or . Electroporation chimeric construct encodes Lhx2-HD and Ldb1-DD (dimerization...
Abstract The most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a G 4 C 2 repeat expansion in intron 1 the C9orf72 gene. This undergoes bidirectional transcription to produce sense antisense RNA species. Both antisense-derived RNAs undergo repeat-associated non-AUG translation all reading frames generate five distinct dipeptide proteins (DPRs). Importantly, toxicity has been associated with repeat-derived DPRs. suggests targeting may...
Abstract Bipolar disorder (BD) is a severe mental illness that can result from neurodevelopmental aberrations, particularly in familial BD, which may include causative genetic variants. In the present study, we derived cortical organoids BD patients and healthy (control) individuals clinically dense family Indian population. Our data reveal patient show anomalies, including organisational, proliferation migration defects. The reduction both number of neuroepithelial buds/cortical rosettes...
Chromatin regulation plays a crucial role in neocortical neurogenesis, and mutations chromatin modifiers are linked to neurodevelopmental disorders. RBBP4 is core subunit of several chromatin-modifying complexes; however, its functional genome-wide occupancy profile the primordium unknown. To address this, we performed knockdown using CRISPR/Cas9 on progenitors derived from mice both sexes at embryonic age 12.5 during deep-layer neurogenesis. Our study demonstrates that downregulation E12.5...
In the developing cerebral cortex, sequential transcriptional programs take neuroepithelial cells from proliferating progenitors to differentiated neurons with unique molecular identities.The regulatory changes that occur in chromatin of are not well understood.During deep layer neurogenesis, we show transcription factor LHX2 binds distal elements Fezf2 and Sox11, critical determinants neuron subtype identity mouse neocortex.We demonstrate nucleosome remodeling histone deacetylase complex...
Abstract Neurogenesis begins with neural stem cells undergoing symmetric proliferative divisions to expand and then switching asymmetric differentiative generate neurons in the developing brain. Chromatin regulation plays a critical role this switch. Histone lysine-specific demethylase LSD1 demethylates H3K4me1/2 H3K9me1/2 but mechanisms of its global regulatory functions human neuronal development remain unclear. We performed genome-wide ChIP-seq occupancy, RNA-seq, upon inhibition identify...
We established an efficient cell culture assay that permits combinatorial genetic perturbations in hippocampal progenitors to examine cell-autonomous mechanisms of fate specification. The procedure begins with ex vivo electroporation isolated, intact embryonic brains, a manner similar utero but greatly improved access and targeting. electroporated region is then dissected transiently maintained organotypic explant culture, followed by dissociation plating cells on coverslips for vitro...