Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins.

Receptors of the Eph family and their ligands (ephrins) mediate developmental vascular assembly and direct axonal guidance. Migrating cell processes identify appropriate targets within migratory fields based on topographically displayed ephrin gradients. Here, EphB1 regulated cell attachment by discriminating the density at which ephrin-B1 was displayed on a reconstituted surface. EphB1-ephrin-B1 engagement did not promote cell attachment through mechanical tethering, but did activate integrin-mediated attachment. In endothelial cells, attachment to RGD peptides or fibrinogen was mediated through alphavbeta3 integrin. EphB1 transfection conferred ephrin-B1-responsive activation of alpha5beta1 integrin-mediated cell attachment in human embryonic kidney cells. Activation-competent but signaling-defective EphB1 point mutants failed to stimulate ephrin-B1 dependent attachment. These findings lead us to propose that EphB1 functions as a 'ligand density sensor' to signal integrin-mediated cell-matrix attachment.

An extracytoplasmic function sigma factor operon regulates Myxococcus xanthus developmental gene expression

Myxococcus xanthus is a Gram-negative soil bacterium that undergoes multicellular development when high-density cells are starved on a solid surface. Expression of the 4445 gene, predicted to encode a periplasmic protein, commences 1.5 h after the initiation of development and requires starvation and high density conditions. Addition of crude or boiled supernatant from starving high-density cells restored 4445 expression to starving low-density cells. Addition of L-threonine or L-isoleucine to starving low-density cells also restored 4445 expression, indicating that the high-density signaling activity present in the supernatant might be composed of extracellular amino acids or small peptides. To investigate the circuitry integrating these starvation and high-density signals, the cis- and trans-acting elements controlling 4445 expression were identified. The 4445 transcription start site was determined by primer extension analysis to be 58 by upstream of the predicted translation start site. The promoter region contained a consensus sequence characteristic of e&barbelow;xtrac&barbelow;ytoplasmic f&barbelow;unction (ECF) sigma factor-dependent promoters, suggesting that 4445 expression might be regulated by an ECF sigma factor-dependent pathway, which are known to respond to envelope stresses. The small size of the minimum regulatory region, identified by 5′-end deletion analysis as being only 66 by upstream of the transcription start site, suggests that RNA polymerase could be the sole direct regulator of 4445 expression. To identify trans-acting negative regulators of 4445 expression, a strain containing a 4445-lacZ was mutagenized using the Himar1-tet transposon. The four transposon insertions characterized mapped to an operon encoding a putative ECF sigma factor, ecfA; an anti-sigma factor, reaA; and a negative regulator, reaB. The reaA and the reaB mutants expressed 4445 during growth and development at levels almost 100-fold higher than wild type, indicating that these genes encode negative regulators. The ecfA mutant expressed 4445-lacZ at basal levels, indicating that ecfA is a positive regulator. High Mg2+ concentrations over-stimulated this ecfA pathway possibly due to the depletion of exopolysaccharides and assembled type IV pili. These data indicate that the ecfA operon encodes a new regulatory stress pathway that integrates and transduces starvation and cell density cues during early development and is also responsive to cell-surface alterations.^

Behavioral Implications of Knockout for the Dyslexia-Risk Gene Dcdc2 in Mice

Several genetic linkage and epidemiological studies have provided strong evidence that DCDC2 is a candidate gene for developmental dyslexia, a disorder that impairs a person’s reading ability despite adequate intelligence, education, and socio-economic status. Studies investigating embryonic intra-ventricular RNA interference (RNAi) of Dcdc2, a rat homolog of the DCDC2 gene in humans, indicate disruptions in neuronal migration in the rat cortex during development. Interestingly, these anatomical anomalies are consistent with post mortem histological analysis of human dyslexic patients. Other rodent models of cortical developmental disruption have shown impairment in rapid auditory processing and learning maze tasks in affected subjects. The current study investigates the rapid auditory processing abilities of mice heterozygous for Dcdc2 (one functioning Dcdc2 allele) and mice with a homozygous knockout of Dcdc2 (no functioning Dcdc2 allele). It is important to note that this genetic model for behavioral assessment is still in the pilot stage. However, preliminary results suggest that mice with a genetic mutation of Dcdc2 have impaired rapid auditory processing, as well as non-spatial maze learning and memory ability, as compared to wildtypes. By genetically knocking out Dcdc2 in mice, behavioral features associated with Dcdc2 can be characterized, along with other neurological abnormalities that may arise due to the loss of the functioning gene.

Elevated pCO2 causes developmental delay in early larval Pacific oysters, Crassostrea gigas

Increasing atmospheric CO2 equilibrates with surface seawater, elevating the concentration of aqueous hydrogen ions. This process, ocean acidification, is a future and contemporary concern for aquatic organisms, causing failures in Pacific oyster (Crassostrea gigas) aquaculture. This experiment determines the effect of elevated pCO2 on the early development of C. gigas larvae from a wild Pacific Northwest population. Adults were collected from Friday Harbor, Washington, USA (48°31.7' N, 12°1.1' W) and spawned in July 2011. Larvae were exposed to Ambient (400 µatm CO2), MidCO2 (700 µatm), or HighCO2 (1,000 µatm). After 24 h, a greater proportion of larvae in the HighCO2 treatment were calcified as compared to Ambient. This unexpected observation is attributed to increased metabolic rate coupled with sufficient energy resources. Oyster larvae raised at HighCO2 showed evidence of a developmental delay by 3 days post-fertilization, which resulted in smaller larvae that were less calcified.

Developmental plasticity of CNS microglia

Microglia arise from CD45+ bone marrow precursors that colonize the fetal brain and play a key role in central nervous system inflammatory conditions. We report that parenchymal microglia are uncommitted myeloid progenitors of immature dendritic cells and macrophages by several criteria, including surface expression of “empty” class II MHC protein and their cysteine protease (cathepsin) profile. Microglia express receptors for stem cell factor and can be skewed toward more dendritic cell or macrophage-like profiles in response to the lineage growth factors granulocyte/macrophage colony-stimulating factor or macrophage colony-stimulating factor. Thus, in contrast to other organs, where terminally differentiated populations of resident dendritic cells and/or macrophages outnumber colonizing precursors, the majority of microglia within the brain remain in an undifferentiated state.

Environmental induction and genetic control of surface antigen switching in the nematode Caenorhabditis elegans.

Nematodes can alter their surface coat protein compositions at the molts between developmental stages or in response to environmental changes; such surface alterations may enable parasitic nematodes to evade host immune defenses during the course of infection. Surface antigen switching mechanisms are presently unknown. In a genetic study of surface antigen switching, we have used a monoclonal antibody, M37, that recognizes a surface antigen on the first larval stage of the free-living nematode Caenorhabditis elegans. We demonstrate that wild-type C. elegans can be induced to display the M37 antigen on a later larval stage by altering the growth conditions. Mutations that result in nonconditional display of this antigen on all four larval stages fall into two classes. One class defines the new gene srf-6 II. The other mutations are in previously identified dauer-constitutive genes involved in transducing environmental signals that modulate formation of the dauer larva, a developmentally arrested dispersal stage. Although surface antigen switching is affected by some of the genes that control dauer formation, these two process can be blocked separately by specific mutations or induced separately by environmental factors. Based on these results, the mechanisms of nematode surface antigen switching can now be investigated directly.

Rapid appearance and asymmetric distribution of glucose transporter SGTP4 at the apical surface of intramammalian-stage Schistosoma mansoni.

Adult Schistosoma mansoni blood flukes reside in the mesenteric veins of their vertebrate hosts, where they absorb immense quantities of glucose through their tegument by facilitated diffusion. Previously, we obtained S. mansoni cDNAs encoding facilitated-diffusion schistosome glucose transporter proteins 1 and 4 (SGTP1 and SGTP4) and localized SGTP1 to the basal membranes of the tegument and the underlying muscle. In this study, we characterize the expression and localization of SGTP4 during the schistosome life cycle. Antibodies specific to SGTP4 appear to stain only the double-bilayer, apical membranes of the adult parasite tegument, revealing an asymmetric distribution relative to the basal transporter SGTP1. On living worms, SGTP4 is available to surface biotinylation, suggesting that it is exposed at the hose-parasite interface. SGTP4 is detected shortly after the transformation of free-living, infectious cercariae into schistosomula and coincides with the appearance of the double membrane. Within 15 min after transformation, anti-SGTP4 staining produces a bright, patchy distribution at the surface of schistosomula, which becomes contiguous over the entire surface of the schistosomula by 24 hr after transformation. SGTP4 is not detected in earlier developmental stages (eggs, sporocysts, and cercariae) that do not possess the specialized double membrane. Thus, SGTP4 appears to be expressed only in the mammalian stages of the parasite's life cycle and specifically localized within the host-interactive, apical membranes of the tegument.

Putting teeth into the developmental origins hypothesis: A longitudinal study of early childhood malnutrition, enamel hypoplasia and adolescent health in Amazonian Bolivia

Thesis (Ph.D.)--University of Washington, 2016-06

Identification of candidate genes for dyslexia susceptibility on chromosome 18

Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Methodology/Principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

Comments on 'The Dyslexia Ecosystem':A reply to Nicolson

The central issue facing the dyslexia community, and the underlying theme of Nicolson's 'The Dyslexia Ecosystem' (Nicolson, 2002, Dyslexia, 8, 55-66), is how we can best translate what we know about this particular developmental disorder into practice to give each child the greatest opportunity of acquiring the enabling skill of literacy. To achieve this, and notwithstanding Nicolson's caveat on this point, we have to consider how we can best move from our sphere of expertise to a greater sphere of influence, both as individuals and as a community of research practitioners. In our response, we first consider aspects of Nicolson's general analysis of 'The Dyslexia Ecosystem' and then examine some of the specific objectives that have been proposed. Copyright © 2002 John Wiley & Sons, Ltd.

Dyslexia - towards diagnosis : the implications of corical laterality for children's reading difficulties

Dyslexia as a concept is defined and reviewed in a context of psychological, neurological and educational processes. In the present investigation these processes are recognised but emphasis is placed on dyslexia as a phenomenon of a written language system. The type of script system involved in the phenomenon is that of an alphabetic code representing phonological elements of language In script form related to meaning. The nature of this system is viewed In the light of current linguistic and psycholinguistic studies. These studies based as they are on an analysis of underlying written language structures provide a framework for examining the arbitrary and rule-governed system which a young child is expected to acquire. There appear to be fundamental implications for reading, spelling and writing processes; for example an alphabetic system requires recognition of consistent script-phonetic relationships, 'mediated word identification' and in particular uni-directional sensory and motor modes of perceiving. These are critical maturational factors in the young learner. The skills needed by the child for decoding and encoding such a phonemic script are described in a psychological and neuropsychological framework. Evidence for individual differences in these skills is noted and the category of the dyslexic-type learner emerges. Incidence is related to the probabilities of individual differences in lateralisation of brain function not favouring the acquisition of our script system In some cases. Dyslexia is therefore regarded as a primary difficulty consequent upon the incompatibility between:the written language system itself and the intrinsic, developmental skills of an individual's perceptual/motor system. It is recognised that secondary stresses e.g. socio-cultural deprivation, low intellectual potential or emotional trauma can further inhibit the learning process. Symptomology of a dyslexic syndrome is described.. The symptomology is seen by the writer to constitute a clinical entity. a specific category of learning difficulty for which predictive and diagnostic procedure could be devised for classroom use. Consequently an index of relevant test items has been compiled, based upon key clinical experiences and theoretical writings. This instrument knovn as the Aston Index is presented and discussed. The early stages of validation are reported and the proposed longtitudinal studies are described. The aim is to give teachers in the classroom the power and understanding to plan more effectively the earliest stages of teaching and learning; in particular to provide the means of matching the nature of the skill to be acquired with the underlying developmental patterns of each individual learner.

A psychological investigation into the relationship between hemispheric functioning and specific written language difficulties (dyslexia), using pharmaceutical intervention techniques

This thesis attempts a psychological investigation of hemispheric functioning in developmental dyslexia. Previous work using neuropsychological methods with developmental dyslexics is reviewed ,and original work is presented both of a conventional psychometric nature and also utilising a new means of intervention. At the inception of inquiry into dyslexia, comparisons were drawn between developmental dyslexia and acquired alexia, promoting a model of brain damage as the common cause. Subsequent investigators found developmental dyslexics to be neurologically intact, and so an alternative hypothesis was offered, namely that language is abnormally localized (not in the left hemisphere). Research in the last decade, using the advanced techniques of modern neuropsychology, has indicated that developmental dyslexics are probably left hemisphere dominant for language. The development of a new type of pharmaceutical prep~ration (that appears to have a left hemisphere effect) offers an oppertunity to test the experimental hypothesis. This hypothesis propounds that most dyslexics are left hemisphere language dominant, but some of these language related operations are dysfunctioning. The methods utilised are those of psychological assessment of cognitive function, both in a traditional psychometric situation, and with a new form of intervention (Piracetam). The information resulting from intervention will be judged on its therapeutic validity and contribution to the understanding of hemispheric functioning in dyslexics. The experimental studies using conventional psychometric evaluation revealed a dyslexic profile of poor sequencing and name coding ability, with adequate spatial and verbal reasoning skills. Neuropsychological information would tend to suggest that this profile was indicative of adequate right hemsiphere abilities and deficits in some left hemsiphere abilities. When an intervention agent (Piracetam) was used with young adult dyslexics there were improvements in both the rate of acquisition and conservation of verbal learning. An experimental study with dyslexic children revealed that Piracetam appeared to improve reading, writing and sequencing, but did not influence spatial abilities. This would seem to concord with other recent findings, that deve~mental dyslexics may have left hemisphere language localisation, although some of these language related abilities are dysfunctioning.

Childhood auditory processing disorder as a developmental disorder:the case for a multi-professional approach to diagnosis and management

Auditory processing disorder (APD) is diagnosed when a patient presents with listening difficulties which can not be explained by a peripheral hearing impairment or higher-order cognitive or language problems. This review explores the association between auditory processing disorder (APD) and other specific developmental disorders such as dyslexia and attention-deficit hyperactivity disorder. The diagnosis and aetiology of APD are similar to those of other developmental disorders and it is well established that APD often co-occurs with impairments of language, literacy, and attention. The genetic and neurological causes of APD are poorly understood, but developmental and behavioural genetic research with other disorders suggests that clinicians should expect APD to co-occur with other symptoms frequently. The clinical implications of co-occurring symptoms of other developmental disorders are considered and the review concludes that a multi-professional approach to the diagnosis and management of APD, involving speech and language therapy and psychology as well as audiology, is essential to ensure that children have access to the most appropriate range of support and interventions.

Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia

Aim: Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. Method: Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years). Results: In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified. Interpretation: The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals. © 2013 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.