47 research outputs found
Molecular psychiatry of zebrafish
No full textDue to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research
The role of primary cilia and sonic hedgehog signalling in adrenal development function.
No full textPhDPrimary cilia are sensory organelles found on most vertebrate cells during interphase. They play key roles in development, cell signalling and cancer, and are involved in signal transduction pathways such as Hh and Wnt signalling. The adrenal cortex produces steroid hormones essential for controlling homeostasis and mediating the stress response. Signalling pathways involved in the process of its development and differentiation are still being identified but include Hh and Wnt, and adrenal development is thus likely to require cilia.
I have demonstrated that inhibiting cilia formation, using siRNA targeted to different ciliary components, results in reduced differentiation of the human adrenal carcinoma cell line H295R towards a zona glomerulosa (zG)-like phenotype. These data suggest that primary cilia play a key role in adrenal differentiation, but which signalling pathways are involved still remains unclear. I have also discovered that adrenals from Bardet-Biedl syndrome (BBS) mice, the most prominently studied ciliopathy, have thin capsules, the proposed adrenal stem cell niche, and abnormal histology, while zebrafish embryos injected with morpholinos targeting BBS genes show delayed and reduced expression of ff1b, a marker of interrenal tissue. These data further suggest a role for primary cilia in adrenal development and maintenance.
These studies are the foundation for elucidating the role of primary cilia in the development and function of the adrenal gland, and furthering our understanding of adrenocortical development. This promises to lead to improved management of adrenal dysfunction, and demonstrating that adrenal defects are a characteristic of ciliopathies will potentially inform new strategies for patient care.Medical Research Counci
Regional and subpopulation rules for plasticity in the adult mouse hippocampus
No full textThe aim of my thesis was to elucidate regional and subpopulation rules for structural plasticity in the adult mouse hippocampus, which can provide insights to information processing and memory formation within the hippocampal circuitry.
Previous studies have shown that dorsal, intermediate and ventral hippocampus have distinct coding and behavioural roles, consistent with the distinct afferent and efferent connectivities along the longitudinal (dorsoventral) axis of the hippocampus. In addition, evidence for distinct hippocampal regions has been provided in the form of discrete molecular domains of gene expression across the hippocampus. However, none of these studies has investigated the anatomy and connectivity at the level of individual identified neurons. Also, it still remains unknown whether structural plasticity upon experience and learning may differ along the dorsoventral axis of the hippocampus and across distinct mossy fibre subpopulations.
To address these questions, I mapped granule cell mossy fibre anatomy and connectivity throughout the hippocampus in three “sparse” Thy1 transgenic reporter mice (Lsi1, Lsi2 and Lsi3) that express membrane-targeted GFP in a subset of principal neurons. By combining behavioural and lesion experiments, as well as high-resolution confocal microscopy and gene expression analysis, I provide evidence that distinct regions of the hippocampus (dorsal, intermediate and ventral) and distinct subpopulations of granule cells exhibit different anatomy and connectivity under baseline conditions and upon learning. Using the growth of filopodial synapses that mediate feed-forward inhibition to the network in CA3 as a specific readout for learning, I show that the dorsal hippocampus encodes spatial information and is specifically recruited for spatial learning, while the ventral hippocampus encodes goal-oriented information and is specifically recruited for goal-oriented learning. Moreover, the results reveal objective distinctions at the circuit level between hippocampal-dependent memory and hippocampal-dependent learning. In addition, I provide evidence that distinct granule cell subpopulations respond in unique ways to experience and learning, suggesting that principal neuron subpopulations may have distinct functional roles in hippocampal-dependent learning and memory
Genetic regulation of pituitary gland development in human and mouse
No full textNormal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans
NF1 optic pathway glioma. Analysing risk factors for visual outcome and indications to treat
No full textBackground:
The aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with Neurofibromatosis type 1 associated optic pathway gliomas (NF1-OPG).
Methods:
A multi-disciplinary expert group consisting of ophthalmologists, pediatric neuro-oncologists, neurofibromatosis specialists and neuro-radiologists involved in therapy trials assembled a cohort of children with NF1-OPG from six European countries with complete clinical, imaging and visual outcome datasets. Using methods developed during a consensus workshop, visual and imaging data were reviewed by the expert team and analyzed to identify associations between factors at diagnosis with visual and imaging outcomes.
Results:
83 patients (37 males, 46 females, mean age 5.1±2.6 years; 1-13.1 years) registered in the European treatment-trial SIOP LGG-2004 (recruited 2004-2012) were included. They were either observed or treated (at diagnosis/ after follow-up).
In multivariable analysis, factors present at diagnosis associated with adverse visual outcomes included: multiple visual signs and symptoms (adjOR 8.33, 95%CI 1.9-36.45); abnormal visual behavior (adjOR 4.15, 95%CI 1.20-14.34); new onset of visual symptoms (adjOR 4.04, 95%CI 1.26-12.95) and optic atrophy (adjOR 3.73, 95%CI 1.13-12.53). Squint, posterior visual pathway tumor involvement, and bilateral pathway tumor involvement, showed borderline significance. Treatment appeared to reduce tumor size but improved vision in only 10/45 treated patients. Children with visual deterioration after primary observation are more likely to improve with treatment than children treated at diagnosis.
Conclusions:
The analysis identified the importance of symptomatology, optic atrophy and history of vision loss as predictive factors for poor visual outcomes in children with NF1-OPG
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Nannoplankton as indicators of climatic variability in the Upper Pliocene
No full textDiscoasters are the remains of an enigmatic group of nannoplankton, whose last representatives disappeared globally at 1.89 Ma. The one million years prior to their extinction has been analysed in high time resolution and a global database has been developed from ten sites in the Atlantic, Indian and Pacific Oceans.
It has been shown that the variability in Discoaster abundance at low latitudes cannot be attributed solely to changes in sea-surface temperature; discoasters were demonstrated to be suppressed at upwelling sites. In combination with global satellite images of phytoplankton blooms (Lewis, 1989) and maps of modern sea-surface temperatures (CLIMAP, 1981), Discoaster abundance variations were interpreted in terms of the interplay between productivity pressure and sea-surface temperature.
Discoasters thrived in the Indian Ocean at Site 709 (4°S) in warm waters with little productivity pressure, whereas Discoaster abundance was suppressed at Sites 677 (l°N) and 662 (l°S) in the Pacific and Atlantic, which although located in warm waters, were affected by upwelling. In addition to the reduced Discoaster abundances associated with upwelling, sea-surface temperature gradients are a significant factor when comparing high and low latitude sites. A marked drop in Discoaster abundance is apparent between 41°N and 56°N (i.e., between Sites 607 and 552).
Relative abundances of species in the Discoaster assemblage revealed clearly their contrasting environmental preferences; D. brouweri was produced under a wide range of conditions, favouring warm, low productivity waters; D. asymmetricus and D. tamalis were produced in higher abundances relative to D. brouweri during cooler, low productivity episodes; D. pentaradiatus showed highest absolute abundance in warm, low productivity waters, although increasing in relative abundance at higher latitudes; D. surculus increased in relative abundance in high productivity regions and in cooler waters. At all sites, though most markedly at higher latitudes, Discoaster abundances declined after 2.4 Ma, when glaciation began in the North Atlantic
The role of highly conserved non-coding DNA sequences in vertebrate development and evolution
No full textPhDComparisons between vertebrate genome sequences, from mammals to fishes, have revealed thousands of conserved non-coding elements (CNEs) that are associated with developmental genes. Interestingly, the vast majority of these CNEs cannot be found in invertebrate genomes by sequence homology. As many CNEs have been demonstrated to act as enhancers in-vivo, it has been postulated that CNEs represent gene regulatory elements with crucial roles in aspects of development that are shared between vertebrates.
To trace the evolution of CNE sequences in vertebrates, a preliminary search for CNEs in the lamprey genome was conducted using the draft lamprey genome sequence. This thesis documents how the CNEs identified in lamprey have been used as a guide to ask questions about the function and evolution of CNEs in the vertebrate lineage. Through the combined use of comparative genomics and developmental biology techniques, including a newly developed reporter assay for sea lamprey embryos, crucial first steps have been taken toward systematically de-coding these ancient gene regulatory elements. Special attention is paid toward utilising the low sequence identity of lamprey CNEs for „phylogenetic footprinting‟, an approach which uncovers striking enrichment of CNEs for a set of motifs that are characteristic of Hox-regulated elements. These findings help to establish CNEs within a developmental and evolutionary context.School of Biological and Chemical Sciences Queen Mary University of London
Ribosomal proteins in zebrafish haematopoiesis and human disease
No full textPhDSeveral congenital disorders of human haematopoiesis including Diamond-
Blackfan anaemia result from heterozygous loss of genes involved in ribosome
biogenesis. Further, hemizygosity for ribosomal protein gene RPS14 has been
implicated in the pathogenesis of myelodysplastic syndrome with loss of 5q,
suggesting that genes involved in ribosome biogenesis may act as both
haploinsufficient tumour suppressors and regulators of normal haematopoiesis.
Ribosome biogenesis is highly conserved through evolution and readily studied in
simple organisms such as yeasts. However the zebrafish provides a wellestablished
genetic model system which is ideally suited to rapid assessment of
vertebrate haematopoiesis. I have therefore used the zebrafish to study genes
involved in ribosome biogenesis and their effects on developmental
haematopoiesis relevant to human disease.
Presented in this work is investigation of the effect of disruption of 4 genes known
to be involved in ribosome biogenesis on zebrafish haematopoiesis. Firstly, I
describe a gene, Dead-box 18 (ddx18), identified in a forward genetic screen,
whose disruption results in defective haematopoiesis and embryonic lethality.
Secondly, I have studied the effects of loss of zebrafish orthologues of the human
nucleophosmin gene (NPM1), the most frequently mutated gene in human acute
myeloid leukaemia. Loss of Npm1 resulted in aberrant numbers of myeloid cells.
Heterologous overexpression of mutated NPM1(NPMc+) resulted in increased
production of haematopoietic stem cells suggesting a role for NPMc+ in
pathogenesis of AML. Finally, I have shown that loss of Rps14 and Rps19 result
in anaemia in developing zebrafish and have investigated p53-independent
mechanisms for this effect.
The findings described herein demonstrate that disruption of normal ribosome
biogenesis frequently results in abnormal developmental haematopoiesis. Further
genetic assessment of these tissue-specific pathways deregulated by loss of
normal ribosome function may represent an important common mechanism
underlying the pathogenesis of congenital and acquired disorders of
haematopoiesis, and may provide novel pathways for therapeutic targeting
An Improved Measurement of B(0)-(B)Bar(0) Mixing in Z(0) Decays
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26830___.PDF (Publisher’s version ) (Open Access
LDLR-Gene therapy for familial hypercholesterolaemia: Problems, progress, and perspectives
No full textCoronary artery diseases (CAD) inflict a heavy economical and social burden on most populations and contribute significantly to their morbidity and mortality rates. Low-density lipoprotein receptor (LDLR) associated familial hypercholesterolemia (FH) is the most frequent Mendelian disorder and is a major risk factor for the development of CAD. To date there is no cure for FH. The primary goal of clinical management is to control hypercholesterolaemia in order to decrease the risk of atherosclerosis and to prevent CAD. Permanent phenotypic correction with single administration of a gene therapeutic vector is a goal still needing to be achieved. The first ex vivo clinical trial of gene therapy in FH was conducted nearly 18 years ago. Patients who had inherited LDLR gene mutations were subjected to an aggressive surgical intervention involving partial hepatectomy to obtain the patient's own hepatocytes for ex vivo gene transfer with a replication deficient LDLR-retroviral vector. After successful re-infusion of transduced cells through a catheter placed in the inferior mesenteric vein at the time of liver resection, only low-level expression of the transferred LDLR gene was observed in the five patients enrolled in the trial. In contrast, full reversal of hypercholesterolaemia was later demonstrated in in vivo preclinical studies using LDLR-adenovirus mediated gene transfer. However, the high efficiency of cell division independent gene transfer by adenovirus vectors is limited by their short-term persistence due to episomal maintenance and the cytotoxicity of these highly immunogenic viruses. Novel long-term persisting vectors derived from adeno-associated viruses and lentiviruses, are now available and investigations are underway to determine their safety and efficiency in preparation for clinical application for a variety of diseases. Several novel non-viral based therapies have also been developed recently to lower LDL-C serum levels in FH patients. This article reviews the progress made in the 18 years since the first clinical trial for gene therapy of FH, with emphasis on the development, design, performance and limitations of viral based gene transfer vectors used in studies to ameliorate the effects of LDLR deficiency
