A5086578496- Genetics and Neurodevelopmental Disorders
- Neurogenesis and neuroplasticity mechanisms
- Autism Spectrum Disorder Research
- Single-cell and spatial transcriptomics
- Developmental Biology and Gene Regulation
- MicroRNA in disease regulation
- Genomics and Chromatin Dynamics
- Pluripotent Stem Cells Research
- Renal and related cancers
- Animal Genetics and Reproduction
- FOXO transcription factor regulation
- Congenital heart defects research
- Axon Guidance and Neuronal Signaling
- Zebrafish Biomedical Research Applications
- Epigenetics and DNA Methylation
- Gene Regulatory Network Analysis
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Molecular Biology Techniques and Applications
- CRISPR and Genetic Engineering
- Gene expression and cancer classification
- ATP Synthase and ATPases Research
- Cancer-related molecular mechanisms research
- Ubiquitin and proteasome pathways
- Bioinformatics and Genomic Networks
University of Edinburgh
2018-2025
Simons Foundation
2018-2021
Simons Initiative for the Developing Brain
2018-2021
ABSTRACT The cerebral cortex contains an enormous number of neurons, allowing it to perform highly complex neural tasks. Understanding how these neurons develop at the correct time and place in accurate numbers constitutes a major challenge. Here, we demonstrate novel role for Gli3, key regulator cortical development, neurogenesis. We show that onset neuron formation is delayed Gli3 conditional mouse mutants. Gene expression profiling cell cycle measurements indicate shortening G1 S phases...
The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and expressed by neurons glia in mammalian brain. Loss FMRP leads to fragile syndrome (FXS), a common inherited form intellectual disability autism. While most research has been focusing on neuronal contribution FXS pathophysiology, role glia, particularly oligodendrocytes, largely unknown. individuals are characterized white matter changes, which imply impairments...
The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence cells to respond such signals. In developing cerebral cortex, progenitors generate only glutamatergic excitatory neurons despite being exposed with potential initiate production other neuronal types, suggesting that their is limited. Here, we tested hypothesis this limitation due expression transcription factor Pax6. We used bulk...
Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility one the hallmarks FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore neural correlates this cognitive inflexibility, we used rat model (Fmr1-/y).We recorded from CA1 in Fmr1-/y WT littermates over six 10-min exploration sessions environment-three per day (ITI 10 min). Our recordings yielded 288 246...
Abstract Background Autism spectrum condition or ‘autism’ is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in cerebral cortex hypothesised to be critical for aetiology of autism making improved understanding how impact on development these cells an important area research. In current study we aim combine bioinformatics analysis human foetal gene expression data anatomical electrophysiological...
Thalamocortical axons (TCAs) cross several tissues on their journey to the cortex. Mechanisms must be in place along route ensure they connect with targets an orderly fashion. The ventral telencephalon acts as instructive tissue, but importance of diencephalon TCA mapping is unknown. We report that disruption diencephalic development by Pax6 deletion results a thalamocortical projection containing errors. used conditional mutagenesis test whether these errors are due pioneer projections from...
Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied models of these disorders, however differences fear response behaviours often overlooked. We aim to examine behaviour its cellular underpinnings a rat model ASD/ID lacking Nlgn3. This study uses range behavioural tests understand Nlgn3-/y rats. Following this, we examined physiological this neurons...
Abstract The transcription factor PAX6 is a crucial regulator of multiple aspects embryonic forebrain development. Its well-known roles in mice include regulating differentiation excitatory and inhibitory neurons the cortex. PAX6’s during human development are less well understood. Using cerebral organoids, we investigated neurodevelopment. Homozygous mutant ( -/- ) organoids were larger than controls contained cell types not found +/+ controls. These cells exhibited clear transcriptomic...
Pax6 is a well-known regulator of early neuroepithelial progenitor development. Its constitutive loss has particularly strong effect on the developing prethalamus, causing it to become extremely hypoplastic. To overcome this difficulty in studying long-term consequences for prethalamic development, we used conditional mutagenesis delete at onset neurogenesis and studied developmental potential mutant neurons vitro. We found that affected their rates neurite elongation, location length axon...
ABSTRACT The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence cells to respond such signals. In developing cerebral cortex, progenitors generate only glutamatergic excitatory neurons despite being exposed with potential initiate production other neuronal types, suggesting that their is limited. Here we tested hypothesis this limitation due expression transcription factor Pax6. We used...
Abstract A key step in understanding the results of biological experiments is visualization data. Many laboratory contain a range measurements that exist within hierarchy interdependence. An automated and facile way to visualize interrogate such multilevel data, across many experimental variables, would (i) lead improved results, (ii) help avoid misleading interpretation statistics (iii) easily identify outliers sources batch confounding effects. While excellent graphing solutions already...
The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and expressed by neurons glia in mammalian brain. Loss FMRP leads to Syndrome (FXS), a common inherited form intellectual disability autism. While most research has been focusing on neuronal contribution FXS pathophysiology, role glia, particularly oligodendrocytes, largely unknown. individuals are characterised white matter changes which imply impairments...
ABSTRACT Pax6 is a well-known regulator of early neuroepithelial progenitor development. Its constitutive loss has particularly strong effect on the developing prethalamus, causing it to become extremely hypoplastic. To overcome this difficulty in studying long-term consequences for prethalamic development, we used conditional mutagenesis delete at onset neurogenesis and studied developmental potential mutant neurons vitro. We found that affected their rates neurite elongation, location...
Summary Differences in the growth and maturation of diverse forebrain tissues depends on region-specific transcriptional regulation. Individual transcription factors act simultaneously multiple regions that develop very differently, raising questions about extent to which their actions vary regionally. We found factor Pax6 affects transcriptomes balance between proliferation differentiation opposite directions murine diencephalon versus cortex. tested several possible mechanisms explain...
Abstract Thalamocortical axons (TCAs) cross several tissues on their journey to the cortex. Mechanisms must be in place along route ensure they connect with targets an orderly fashion. The ventral telencephalon acts as instructive tissue, but importance of diencephalon TCA mapping is unknown. We report that disruption diencephalic development by Pax6 deletion results a thalamocortical projection containing errors. used conditional mutagenesis test whether these errors are due pioneer...
Differences in the growth and maturation of diverse forebrain tissues depend on region-specific transcriptional regulation. Individual transcription factors act simultaneously multiple regions that develop very differently, raising questions about extent to which their actions vary regionally. We found factor Pax6 affects transcriptomes balance between proliferation differentiation opposite directions diencephalon versus cerebral cortex. tested several possible mechanisms explain Pax6’s...
Abstract A key step in understanding the results of biological experiments is visualization data. Many laboratory contain a range measurements that exist within hierarchy interdependence. An automated way to visualise and interrogate experimental data would: 1) lead improved results, 2) help determine which statistical tests should be performed, 3) easily identify outliers sources batch effects. Unfortunately, existing graphing solutions often demand expertise programming, require...
During forebrain development, the transcription factor PAX6 is highly expressed by progenitors in dorsal telencephalon (dTel) i.e. primitive cerebral cortex with a sharp boundary at pallial-subpallial boundary, thereby establishing dorso-ventral patterning of and regulating generation cortical glutamatergic neurons. Strikingly, removal Pax6 led to diversion away from identity subset indicated ectopic gene expression. We postulate that confers fate preventing them responding signaling cues...
Summary Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied models of these disorders, however differences fear response behaviours often overlooked. Whilst examining a rat model ASD/ID lacking Nlgn3 , we observed that they display greater propensity to exhibit flight responses contrast classic freezing seen wildtypes during fearful situations....
ABSTRACT Autism spectrum condition or ‘autism’ is associated with numerous monogenic and polygenic genetic risk factors including the 16p11.2 microdeletion. A central question what neural cells are affected. To systematically investigate we analysed single cell transcriptomes from gestational week (GW) 8-26 human foetal prefrontal cortex identified a subset of interneurons (INs) first appearing at GW23 enriched expression disproportionately large fraction factor transcripts. This suggests...
Abstract Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and Autism Spectrum Disorder. Cognitive inflexibility one the hallmarks FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore neural correlates this cognitive inflexibility, we used rat model ( Fmr1 -/y ), recorded from CA1 region hippocampus while animals habituated in environment for two consecutive days. On first day exploration, firing rate...