Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • Cellular requirements for building a retinal neuropil.

    10 May 2018

    How synaptic neuropil is formed within the CNS is poorly understood. The retinal inner plexiform layer (IPL) is positioned between the cell bodies of amacrine cells (ACs) and retinal ganglion cells (RGCs). It consists of bipolar cell (BC) axon terminals that synapse on the dendrites of ACs and RGCs intermingled with projections from Müller glia (MG). We examined whether any of these cellular processes are specifically required for the formation of the IPL. Using genetic and pharmacological strategies, we eliminated RGCs, ACs, and MG individually or in combination. Even in the absence of all of these partner cells, an IPL-like neuropil consisting of only BC axon terminals still forms, complete with presynaptic specializations and sublaminar organization. Previous studies have shown that an IPL can form in the complete absence of BCs; therefore, we conclude that neither presynaptic nor postsynaptic processes are individually essential for the formation of this synaptic neuropil.

  • Origin and determination of inhibitory cell lineages in the vertebrate retina.

    10 May 2018

    Multipotent progenitors in the vertebrate retina often generate clonally related mixtures of excitatory and inhibitory neurons. The postmitotically expressed transcription factor, Ptf1a, is essential for all inhibitory fates in the zebrafish retina, including three types of horizontal and 28 types of amacrine cell. Here, we show that specific types of inhibitory neurons arise from the cell-autonomous influence of Ptf1a in the daughters of fate-restricted progenitors, such as Ath5 or Vsx1/2-expressing progenitors, and that in the absence of Ptf1a, cells that would have become these specific inhibitory subtypes revert to the histogenetically appropriate excitatory subtypes of the same lineage. Altered proportions of amacrine subtypes respecified by the misexpression of Ptf1a in the Ath5 lineage suggest that Ath5-expressing progenitors are biased, favoring the generation of some subtypes more than others. Yet the full array of inhibitory cell subtypes in Ath5 mutants implies the existence of Ath5-independent factors involved in inhibitory cell specification. We also show that an extrinsic negative feedback on the expression of Ptf1a provides a control mechanism by which the number of any and all types of inhibitory cells in the retina can be regulated in this lineage-dependent way.

  • Growth-factor-dependent phosphorylation of Bim in mitosis.

    15 February 2018

    The regulation of survival and cell death is a key determinant of cell fate. Recent evidence shows that survival and death machineries are regulated along the cell cycle. In the present paper, we show that BimEL [a BH3 (Bcl-2 homology 3)-only member of the Bcl-2 family of proteins; Bim is Bcl-2-interacting mediator of cell death; EL is the extra-long form] is phosphorylated in mitosis. This post-translational modification is dependent on MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase) and growth factor signalling. Interestingly, FGF (fibroblast growth factor) signalling seems to play an essential role in this process, since, in the presence of serum, inhibition of FGF receptors abrogated phosphorylation of Bim in mitosis. Moreover, we have shown bFGF (basic FGF) to be sufficient to induce phosphorylation of Bim in serum-free conditions in any phase of the cell cycle, and also to significantly rescue cells from serum-deprivation-induced apoptosis. Our results show that, in mitosis, Bim is phosphorylated downstream of growth factor signalling in a MEK-dependent manner, with FGF signalling playing an important role. We suggest that phosphorylation of Bim is a decisive step for the survival of proliferating cells.

  • Tsukushi modulates Xnr2, FGF and BMP signaling: regulation of Xenopus germ layer formation.

    29 March 2018

    BACKGROUND: Cell-cell communication is essential in tissue patterning. In early amphibian development, mesoderm is formed in the blastula-stage embryo through inductive interactions in which vegetal cells act on overlying equatorial cells. Members of the TGF-beta family such as activin B, Vg1, derrière and Xenopus nodal-related proteins (Xnrs) are candidate mesoderm inducing factors, with further activity to induce endoderm of the vegetal region. TGF-beta-like ligands, including BMP, are also responsible for patterning of germ layers. In addition, FGF signaling is essential for mesoderm formation whereas FGF signal inhibition has been implicated in endoderm induction. Clearly, several signaling pathways are coordinated to produce an appropriate developmental output; although intracellular crosstalk is known to integrate multiple pathways, relatively little is known about extracellular coordination. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that Xenopus Tsukushi (X-TSK), a member of the secreted small leucine rich repeat proteoglycan (SLRP) family, is expressed in ectoderm, endoderm, and the organizer during early development. We have previously reported that X-TSK binds to and inhibits BMP signaling in cooperation with chordin. We now demonstrate two novel interactions: X-TSK binds to and inhibits signaling by FGF8b, in addition to binding to and enhancement of Xnr2 signaling. This signal integration by X-TSK at the extracellular level has an important role in germ layer formation and patterning. Vegetally localized X-TSK potentiates endoderm formation through coordination of BMP, FGF and Xnr2 signaling. In contrast, X-TSK inhibition of FGF-MAPK signaling blocks ventrolateral mesoderm formation, while BMP inhibition enhances organizer formation. These actions of X-TSK are reliant upon its expression in endoderm and dorsal mesoderm, with relative exclusion from ventrolateral mesoderm, in a pattern shaped by FGF signals. CONCLUSIONS/SIGNIFICANCE: Based on our observations, we propose a novel mechanism by which X-TSK refines the field of positional information by integration of multiple pathways in the extracellular space.

  • How variable clones build an invariant retina.

    13 June 2018

    A fundamental question in developmental neuroscience is how a collection of progenitor cells proliferates and differentiates to create a brain of the appropriate size and cellular composition. To address this issue, we devised lineage-tracing assays in developing zebrafish embryos to reconstruct entire retinal lineage progressions in vivo and thereby provide a complete quantitative map of the generation of a vertebrate CNS tissue from individual progenitors. These lineage data are consistent with a simple model in which the retina is derived from a set of equipotent retinal progenitor cells (RPCs) that are subject to stochastic factors controlling lineage progression. Clone formation in mutant embryos reveals that the transcription factor Ath5 acts as a molecular link between fate choice and mode of cell division, giving insight into the elusive molecular mechanisms of histogenesis, the conserved temporal order by which neurons of different types exit the cell cycle.

  • The F-box protein Cdc4/Fbxw7 is a novel regulator of neural crest development in Xenopus laevis.

    29 March 2018

    BACKGROUND: The neural crest is a unique population of cells that arise in the vertebrate ectoderm at the neural plate border after which they migrate extensively throughout the embryo, giving rise to a wide range of derivatives. A number of proteins involved in neural crest development have dynamic expression patterns, and it is becoming clear that ubiquitin-mediated protein degradation is partly responsible for this. RESULTS: Here we demonstrate a novel role for the F-box protein Cdc4/Fbxw7 in neural crest development. Two isoforms of Xenopus laevis Cdc4 were identified, and designated xCdc4alpha and xCdc4beta. These are highly conserved with vertebrate Cdc4 orthologs, and the Xenopus proteins are functionally equivalent in terms of their ability to degrade Cyclin E, an established vertebrate Cdc4 target. Blocking xCdc4 function specifically inhibited neural crest development at an early stage, prior to expression of c-Myc, Snail2 and Snail. CONCLUSIONS: We demonstrate that Cdc4, an ubiquitin E3 ligase subunit previously identified as targeting primarily cell cycle regulators for proteolysis, has additional roles in control of formation of the neural crest. Hence, we identify Cdc4 as a protein with separable but complementary functions in control of cell proliferation and differentiation.

  • Inhibitory neuron migration and IPL formation in the developing zebrafish retina.

    25 May 2018

    The mature vertebrate retina is a highly ordered neuronal network of cell bodies and synaptic neuropils arranged in distinct layers. Little, however, is known about the emergence of this spatial arrangement. Here, we investigate how the three main types of retinal inhibitory neuron (RIN)--horizontal cells (HCs), inner nuclear layer amacrine cells (iACs) and displaced amacrine cells (dACs)--reach their specific laminar positions during development. Using in vivo time-lapse imaging of zebrafish retinas, we show that RINs undergo distinct phases of migration. The first phase, common to all RINs, is bipolar migration directed towards the apicobasal centre of the retina. All RINs then transition to a less directionally persistent multipolar phase of migration. Finally, HCs, iACs and dACs each undergo cell type-specific migration. In contrast to current hypotheses, we find that most dACs send processes into the forming inner plexiform layer (IPL) before migrating through it and inverting their polarity. By imaging and quantifying the dynamics of HCs, iACs and dACs from birth to final position, this study thus provides evidence for distinct and new migration patterns during retinal lamination and insights into the initiation of IPL formation.

  • The ciliary marginal zone of the zebrafish retina: clonal and time-lapse analysis of a continuously growing tissue.

    13 June 2018

    Clonal analysis is helping us understand the dynamics of cell replacement in homeostatic adult tissues (Simons and Clevers, 2011). Such an analysis, however, has not yet been achieved for continuously growing adult tissues, but is essential if we wish to understand the architecture of adult organs. The retinas of lower vertebrates grow throughout life from retinal stem cells (RSCs) and retinal progenitor cells (RPCs) at the rim of the retina, called the ciliary marginal zone (CMZ). Here, we show that RSCs reside in a niche at the extreme periphery of the CMZ and divide asymmetrically along a radial (peripheral to central) axis, leaving one daughter in the peripheral RSC niche and the other more central where it becomes an RPC. We also show that RPCs of the CMZ have clonal sizes and compositions that are statistically similar to progenitor cells of the embryonic retina and fit the same stochastic model of proliferation. These results link embryonic and postembryonic cell behaviour, and help to explain the constancy of tissue architecture that has been generated over a lifetime.

  • Imbalance of ADHD diagnosis in the US

    23 November 2015

    Higher numbers of diagnosis exist in some affluent populations, while in poor white populations and ethnic minorities there is under-diagnosis, says Professor Ilina Singh

  • It's August! Will Self demolishes psychiatry after intense introspection & finds kind words for Tom Burns

    5 August 2013

    "Early in Our Necessary Shadow, his lucid, humane and in many ways well-balanced account of the nature and meaning of psychiatry, Tom Burns, professor of social psychiatry at Oxford University, makes a supremely telling remark: "I am convinced psychiatry is a major force for good or I would not have spent my whole adult life in it." This is a form of the logical fallacy post hoc ergo propter hoc ("After this, therefore because of this"), and it seems strange that an academic of such standing should so blithely retail it because, of course, if we reverse the statement it makes just as much sense: "Having spent my whole adult life as a psychiatrist I must maintain the conviction that it is a major force for good.""

  • Study finds virtual reality can help treat severe paranoia

    5 May 2016

    Virtual reality can help treat severe paranoia by allowing people to face situations that they fear, an Oxford University study has found. The virtual reality simulations allowed the patients to learn that the situations they feared (such as a crowded tube train) were actually safe.

  • Can psychological therapies help people who self-harm?

    16 May 2016

    A review by the respected Cochrane organisation, and led by Oxford University Professor of Psychiatry Keith Hawton, has found that psychological therapies, more commonly known as 'talking treatments', may help people who self-harm.

  • Success for Cognitive Research Facility as funding renewed

    29 November 2016

    The NIHR Oxford cognitive health Clinical Research Facility has been awarded £3.7m to continue its life-changing work translating innovative research into better treatments for cognitive health.

  • Antipsychotic medication linked to reduced rate of violent crime

    8 May 2014

    In a new study, Dr Seena Fazel, a consultant forensic psychiatrist at Oxford University, found that people who use antipsychotic medicines to treat psychiatric illness were nearly half as likely to commit a violent crime compared with when they are not using it. Only a minority of patients perpetrate crimes, said Dr. Fazel. "But even in this minority, it may be to a large extent a modifiable risk."

  • Elizabeth Braithwaite shortlisted for Medical Research Council’s Max Perutz Science Writing Award

    3 October 2013

    "Oxford University researcher Elizabeth Braithwaite, from the Department of Psychiatry at Warneford Hospital, was among 11 finalists from 200 applicants in the Medical Research Council’s Max Perutz Science Writing Award. She was shortlisted for her article about research she is undertaking into depression during pregnancy" [Oxford Mail, 03/10/2013, p.8]

  • Applications Invited for Wellcome Trust Oxford DPhil Scheme for Psychiatrists

    21 September 2015

    Psychiatrists at any stage in their training in the UK who wish to do a DPhil (PhD) can apply for this prestigious scheme which pays an appropriate clinical salary, fees, and research costs, for three years. Up to four places are available.

  • BBC World Service: Why does funk music make us want to dance?

    14 March 2016

    Professor Morten Kringelbach, from the University of Oxford Department of Psychiatry, explains how we get pleasure from certain kinds of syncopated beats.

  • Congratulations Marco Narajos, Sophie Behrman & Jane Walker !

    24 July 2015

    Marco Narajos, Sophie Behrman & Jane Walker were shortlisted by the Royal College of Psychiatrists for the 'medical student', 'senior trainee' & ‘academic researcher of the year’ award 2015, respectively.