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62
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Introduction
Hi!
I have an interest primarily in the mechanisms involved in interneuron migration and the role of Slit-Robo during development
Skills and Expertise
Current institution
Additional affiliations
October 1998 - October 2003
May 2002 - July 2004
Position
- PostDoc Position
Description
- working on Robo genes, and generation of Robo transgenic mice
Education
October 1990 - July 1995
Publications
Publications (62)
Axon guidance cues direct nerves in the heart during development, disease and regeneration. These cues determine cardiac innervation patterning by regulating the balance between chemo-attraction and chemo-repulsion. However, the role of one of the most crucial ligand-receptor combinations among axon guidance molecules, the Slit chemo-active ligands...
Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy – tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific...
Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's disease (ad). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice...
Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific...
A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs in vertebrates1,2. Nevertheless, we lack a developmental blueprint that integrates the molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development3. Her...
Cortical interneurons are born in the ventral forebrain and migrate tangentially in two streams at the levels of the intermediate zone (IZ) and the pre-plate/marginal zone to the developing cortex where they switch to radial migration before settling in their final positions in the cortical plate. In a previous attempt to identify the molecules tha...
Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice...
Recent genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild-type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-i...
Vascular endothelial growth factor (Vegfa) is essential for promoting the vascularization of the embryonic murine forebrain. In addition, it directly influences neural development, although its role in the forming forebrain is less well elucidated. It was recently suggested that Vegfa may influence the development of GABAergic interneurons, inhibit...
Cortical interneurons are generated in the ganglionic eminences and migrate through the ventral and dorsal telencephalon before finding their final positions within the cortical plate. During early stages of migration, these cells are present in two well-defined streams within the developing cortex. In an attempt to identify candidate genes which m...
Cortical interneurons are generated predominantly in the medial ganglionic eminence of the ventral telencephalon and migrate to the cortex during embryonic development. These cells express neuropilin (Nrp1 and Nrp2) receptors which mediate their response to the chemorepulsive class 3 semaphorin (Sema) ligands. We show here that semaphorins Sema3A a...
Background:
Treatment strategies for breast cancer continue to evolve. No uniformity exists in the UK for the management of node positive breast cancer patients. Most centres continue to use conventional histopathology of sampled sentinel lymph nodes (SLN), which requires delayed axillary clearance in up to 25% of patients. Some use touch imprint...
Cortical interneurons are generated predominantly in the medial ganglionic eminence (MGE) and migrate through the ventral and dorsal telencephalon before finding their final positions within the developing cortical plate. Previously, we demonstrated that interneurons from Robo1 knockout (Robo1(-/-) ) mice contain reduced levels of neuropilin 1 (Nrp...
The mesenchymal cushions lining the early embryonic heart undergo complex remodelling to form the membranous ventricular septum as well as the atrioventricular and semilunar valves in later life. Disruption of this process underlies the most common congenital heart defects. Here, we identified a novel role for Slit-Robo signalling in the developmen...
Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, a...
The elaborate cytoarchitecture of the mammalian neocortex requires the timely production of its constituent pyramidal neurons and interneurons and their disposition in appropriate layers. Numerous chemotropic factors present in the forebrain throughout cortical development play important roles in the orchestration of these events. The Roundabout (R...
En route to the neocortex, interneurons migrate around and avoid the developing striatum. This is due to the chemorepulsive cues of class 3 semaphorins (Sema3A and Sema3F) acting through neuropilin and plexin co-receptors expressed in interneurons. In a recent genetic screen aimed at identifying novel components that may play a role in interneuron...
Rationale:
The Slit-Roundabout (Robo) signaling pathway has pleiotropic functions during Drosophila heart development. However, its role in mammalian heart development is largely unknown.
Objective:
To analyze the role of Slit-Robo signaling in the formation of the pericardium and the systemic venous return in the murine heart.
Methods and resu...
Neuritin 1 (Nrn1 or cpg15-1) is an activity-dependent protein involved in synaptic plasticity during brain development, a process that relies upon neuronal migration. By analyzing Nrn1 expression, we found that it is highly expressed in a mouse model of migrating immortalized neurons (GN11 cells), but not in a mouse model of non-migrating neurons (...
Gonadotropin-releasing hormone (GnRH) neurons are born in the nasal placode and migrate along olfactory and vomeronasal axons to reach the forebrain and settle in the hypothalamus, where they control reproduction. The molecular cues that guide their migration have not been fully identified, but are thought to control either cell movement directly o...
To better understand neuroblastoma differentiation, we used microarray analysis to identify common gene expression changes from three differentiation models. This revealed STMN4 and ROBO2 to be consistently up-regulated in differentiated neuroblastoma cells induced by chromosome 1 transfer, MYCN knockdown, and 9-cis retinoic acid (9cRA). Furthermor...
Patients whose hematopoietic system is compromised by chemo- and/or radiotherapy require transplantation of hematopoietic stem and progenitor cells (HSPCs) to restore hematopoiesis. Successful homing of transplanted HSPCs to the bone marrow (BM) largely depends on their migratory potential, which is critically regulated by the chemokine CXCL12. In...
Laminar organization is a key feature of the mammalian cerebral cortex, but the mechanisms by which final positioning and "inside-out" distribution of neurons are determined remain largely unknown. Here, we demonstrate that Robo1, a member of the family of Roundabout receptors, regulates the correct positioning of layers II/III pyramidal neurons in...
The modulation of cortical activity by GABAergic interneurons is required for normal brain function and is achieved through the immense level of heterogeneity within this neuronal population. Cortical interneurons share a common origin in the ventral telencephalon, yet during the maturation process diverse subtypes are generated that form the chara...
Cortical interneurons originate in the ganglionic eminences of the subpallium and migrate into the cortex in well-defined tangential streams. At the start of corticogenesis, two streams of migrating neurons are evident: a superficial one at the level of the preplate (PPL), and a deeper one at the level of the intermediate zone (IZ). Currently, litt...
Cortical interneurons, generated predominantly in the medial ganglionic eminence, migrate around and avoid the developing striatum in the subpallium en route to the cortex. This is attributable to the chemorepulsive cues of class 3 semaphorins expressed in the striatal mantle and acting through neuropilin (Nrp1 and Nrp2) receptors expressed in thes...
Gamma-aminobutyric acid (GABA)ergic interneurons play a vital role in modulating the activity of the cerebral cortex, and disruptions to their function have been linked to neurological disorders such as schizophrenia and epilepsy. These cells originate in the ganglionic eminences (GE) of the ventral telencephalon and undergo tangential migration to...
The ability of sensory systems to detect and process information from the environment relies on the elaboration of precise connections between sensory neurons in the periphery and second order neurons in the CNS. In mice, the accessory olfactory system is thought to regulate a wide variety of social and sexual behaviors. The expression of the Slit...
Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is an important goal, as such knowledge can help to identify new genes involved in cardiovascular disease. The transcription factor Tbx1 plays a vital role in PAA development and is a major contributor to cardiovascular disease associated with DiGeorge syn...
The developing optic pathway has proven one of the most informative model systems for studying mechanisms of axon guidance. The first step in this process is the directed extension of retinal ganglion cell (RGC) axons within the optic fibre layer (OFL) of the retina towards their exit point from the eye, the optic disc. Previously, we have shown th...
A number of studies in recent years have shown that members of the Roundabout (Robo) receptor family, Robo1 and Robo2, play
significant roles in the formation of axonal tracks in the developing forebrain and in the migration and morphological differentiation
of cortical interneurons. Here, we investigated the expression and function of Robo3 in the...
Axonal projections from the retina to the brain are regulated by molecules including the Slit family of ligands [Thompson, H., Barker, D., Camand, O., Erskine, L., 2006a. Slits contribute to the guidance of retinal ganglion cell axons in the mammalian optic tract. Dev. Biol. 296, 476-484, Thompson, H., Camand, O., Barker, D., Erskine, L., 2006b. Sl...
Cortical interneurons in rodents are generated in the ventral telencephalon and migrate tangentially into the cortex. This process requires the coordinated action of many intrinsic and extrinsic factors. Here we show that Robo1 and Robo2 receptor proteins are dynamically expressed throughout the period of corticogenesis and colocalize with interneu...
Quantification of the number of ectopic motor neurons in chick embryos electroporated in the ventral neural tube with EGFP-shRNAs. Table providing a quantitative analysis of the occurrence of ectopic motor neurons after electroporation of chick embryos in the ventral neural tube with Npn-2, Plexin-A2, MICAL3 EGFP-shRNA or empty vector. Embryos were...
Targeted delivery of EGFP expression plasmids by selective electroporation towards either the ventral neural tube or the neural crest. Confocal micrographs of transverse vibratome sections (75 μm). (a) An example of a HH23 chick embryo electroporated in the ventral neural tube with the pCA-EGFPm5-mU6 plasmid, as detailed in the Materials and method...
Npn-2 B and Npn-2 E shRNA reduce expression of V5-tagged cNpn-2 in HEK cells. Vectors co-expressing EGFP and shRNA targeted at Npn-2 were co-transfected with pcDNA3.1-V5-cNpn-2 [19] at a ratio of 5:1. At 2 days post-transfection, cells were fixed and stained with V5 antibodies. The data show efficient knockdown of V5-tagged Npn-2 with Npn-2 B and N...
Confirmation of knockdown of Plexin mRNAs by ventral targeted shRNA in the chick spinal cord. Embryos were electroporated at E2 (HH stage 13–15) in the ventral neural tube with shRNA vectors targeting (a,b) Plexin-A1, (c,d) Plexin-A2 or (e,f) Plexin-A4. The effect of each shRNA on expression was assessed after 48–54 hours (HH 23–24) by in situ hybr...
Screen of shRNA vectors targeting Npn or Plexin-A receptors in the chick for the ability to induce ectopic motor neuron migration. The prevalence of ectopic motor neurons after ventral electroporation of shRNA vectors targeting plexin-A and neuropilin receptors in the chick was assessed. In a first round of analysis, three different vectors were te...
Table of shRNA target sequences and SFOLD scores (on a 0–20 scale). Note that the Npn-1B and Npn-2 B shRNAs we published previously have a relatively low SFOLD score, yet efficiently reduced expression of their targets [19].
Specificity of knockdown by Plexin-A2 shRNA. An embryo was electroporated at E2 (HH stage 13–15) in the ventral neural tube with an shRNA vector targeting Plexin-A2. The effect at HH stage 23 of shRNA electroporation (a) on expression of (b) Plexin-A1, (c) -A2 and (d) -A4 was assessed on adjacent transverse cryosections of hindlimb region spinal co...
Egr2/Krox-20 expressing BC cells persist in Npn-2 mutant mice. In situ hybridisation for Egr2 on transverse cryosections (30 μm) obtained from E11.5 mouse embryos at hindlimb level. The results show no obvious difference in Egr2 expression in BC cells located at the DREZ or MEP in (a) wild-type, (b) heterozygous or (c) Npn-2 null mice. Bar = 100 μm...
The formation of precise stereotypic connections in sensory systems is critical for the ability to detect and process signals from the environment. In the olfactory system, olfactory sensory neurons (OSNs) project axons to spatially defined glomeruli within the olfactory bulb (OB). A spatial relationship exists between the location of OSNs within t...
Interneurons are an integral part of cortical neuronal circuits. During the past decade, numerous studies have shown that these cells, unlike their pyramidal counterparts that are derived from the neuroepithelium along the lumen of the lateral ventricles, are generated in the ganglionic eminences in the subpallium. They use tangential migratory pat...
Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and you...
Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus play an important role in reproductive function. These cells originate in the nasal compartment and migrate into the basal forebrain in association with olfactory/vomeronasal nerves in embryonic life in rodents. Here, we studied the role of neuropilins and their ligands, semaphorins,...
Background
In developing neurons, somal migration and initiation of axon outgrowth often occur simultaneously and are regulated in part by similar classes of molecules. When neurons reach their final destinations, however, somal translocation and axon extension are uncoupled. Insights into the mechanisms underlying this process of disengagement cam...
The Slit genes encode secreted ligands that regulate axon branching, commissural axon pathfinding and neuronal migration. The principal identified receptor for Slit is Robo (Roundabout in Drosophila). To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene. Homozygot...
Robo3 is a member of the roundabout (Robo) family of proteins that plays a key role in axon guidance and cell migration in the developing nervous system. Recent studies have shown that Robo3 plays a crucial role in controlling axon guidance at the midline of the CNS. Here we describe and compare two human Robo3 isoforms, Robo3A and Robo3B, which di...
The floor plate is known to be a source of repellent signals for cranial motor axons, preventing them from crossing the midline of the hindbrain. However, it is unknown which molecules mediate this effect in vivo. We show that Slit and Robo proteins are candidate motor axon guidance molecules, as Robo proteins are expressed by cranial motoneurons,...
The ventral midline of the central nervous system is an important intermediate target where growing commissural axons either cross and project contralaterally or remain on the same side of the body. New studies on mice and humans show that this decision by commissural axons is largely dependent on Slits, extracellular matrix proteins that are widel...
Robo, the receptor for the midline repellent Slit, is a member of the cell adhesion molecule (CAM) Ig superfamily. We have recently demonstrated that members of the Robo family (Robo1 and Robo2) interact homophilically and heterophilically, thereby functioning to promote neurite outgrowth. Here, we describe a series of in vitro experiments to disse...
The Robo family of molecules is important for axon guidance across the midline during central nervous system (CNS) development in invertebrates and vertebrates. Here we describe the patterns of Robo protein expression in the developing mouse CNS from embryonic day (E) 9.5 to postnatal day (P) 4, as determined by immunohistochemical labeling with an...
The vomeronasal projection conveys information provided by pheromones and detected by neurones in the vomeronasal organ (VNO) to the accessory olfactory bulb (AOB) and thence to other regions of the brain such as the amygdala. The VNO-AOB projection is topographically organised such that axons from apical and basal parts of the VNO terminate in the...
Thesis (Ph. D.)--University of Reading, 1995.
