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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

ATRX Protects Cells Against Replication-Induced Genomic Instability

Ivanochko, Danton January 2016 (has links)
Expansive proliferation of neural progenitor cells (NPCs) is a prerequisite to the temporal waves of neuronal differentiation that generate the six-layered cerebral cortex. NPC expansion places a heavy burden on proteins that regulate chromatin packaging and genome integrity, which is further reflected by the growing number of developmental disorders caused by mutations in chromatin regulators. Accordingly, mutations in ATRX, a chromatin remodelling protein required for heterochromatin maintenance at telomeres and simple repeats, cause the ATR-X syndrome. Here, we demonstrate that proliferating ATRX-null cells accumulate DNA damage, while also exhibiting sensitivity to hydroxyurea-induced replication fork stalling. Specifically, PARP1 hyperactivation and replication-dependent double strand DNA breakage indicated replication fork protection defects, while DNA fiber assays confirmed that ATRX was required to protect replication forks from degradation. Interestingly, inhibition of the exonuclease MRE11 by the small molecule mirin could prevent degradation. Thus, ATRX is required to limit replication stress during NPC expansion.
2

Behavioral alterations in rat offspring following maternal immune activation and CXC chemokine receptor antagonism

2014 September 1900 (has links)
Schizophrenia patients typically exhibit cognitive impairments that directly affect their daily functioning, but are not effectively treated by current antipsychotics. Maternal immune activation (MIA) during pregnancy, which can be triggered by a variety of infectious agents, has been associated with the development of schizophrenia in adult offspring. Epidemiological evidence indicates that elevated maternal levels of the chemokine interleukin- 8 (IL-8) during MIA contribute to the neurodevelopmental alterations underlying the disorder. The present experiments used an animal model of neurodevelopmental disorders to study the effects of MIA and chemokine receptor antagonism on the behavior of rat offspring, with behavioral tests chosen to examine cognitive functions that are typically impaired in human schizophrenia patients. The viral mimetic polyinosinic-polycytidylic acid (polyI:C) (4.0 mg/kg, i.v.) was injected into pregnant Long-Evans (LE) dams on gestational day (GD) 15. Dams were also treated with the three injections of CXCL8(3–72)K11R/G31P (G31P) (500 µg/kg, i.p.), a chemokine receptor antagonist that binds CXCR1 and CXCR2 with high affinity. PolyI:C treatment significantly increased maternal levels of the chemokine CXCL1, the rodent analogue of IL-8 that binds CXCR1 and CXCR2. The offspring of polyI:C-treated dams showed impaired associative recognition memory and multisensory integration, as well as subtle impairments in prepulse inhibition (PPI). G31P administration did not reverse any of the behavioral deficits caused by polyI:C, although G31P did alter PPI during adolescence. Although the present experiments included replications and novel findings for the polyI:C model, the effects of polyI:C were smaller than in other published research. Utilizing animal models that include both genetic and environmental components, as well as more widely targeted anti-inflammatory therapies will likely result in more promising findings in future research.
3

Predicting Developmental Outcomes for Premature Infants: Neurobiologic Risk Score Versus Neurodevelopmental Risk Examination at Neonatal Intensive Care Unit Discharge

Wickremasinghe, Andrea C., Hartman, Tyler K., Voigt, Robert G., Katusic, Slavica K., Weaver, Amy L., Colby, Christopher E., Barbaresi, William J. 01 December 2009 (has links)
Prematurity is associated with poor neurodevelopmental outcomes, and laws mandate the provision of early intervention services to those infants with disability. However, it is often difficult to identify early which infants would benefit most from these services. The Neurobiologic Risk Score (NBRS) and the Neurodevelopmental Risk Exam (NRE) are instruments used to assess infants at near-term corrected age. These instruments have been shown to correlate with later developmental outcomes. However, the environment of the neonatal intensive care unit (NICU) has changed since the NBRS and NRE were first validated, and it is not known whether they are still able to accurately predict future developmental outcomes. The objective of this study was therefore to examine the ability of the NBRS and NRE, both alone and in combination with socio-economic variables, to predict future developmental outcomes in the contemporary NICU. The subjects were 219 neonates of less than 32 weeks' gestational age discharged from the NICU between November 2001 and December 2006 who had undergone both the NBRS and NRE. Infants were assessed at chronological age 6, 12 and 24 months, with developmental quotients being assigned at these ages. Parental socio-economic data were also collected and analysed. The hypothesis was that the NBRS and NRE would be less effective at predicting neurodevelopmental outcomes in the contemporary NICU. The best measure of future developmental outcome is likely to need to include both neurobiological and socio-economic risk factors.
4

The role of AF1q in neural development

Choi, Yeyoon 11 June 2019 (has links)
ALL1-fused gene from chromosome 1q (AF1q) is a novel gene that encodes a 90-amino-acid protein that is unlike any other known proteins. AF1q was first discovered as a fusion partner for mixed-lineage leukemia in a pediatric acute myeloid leukemia. Since its discovery, AF1q has been found to act as an oncogene and has been linked to several solid neoplasms, including thyroid oncocytic tumors, breast cancer, testicular cancer, and colorectal cancer. AF1q is also upregulated in several hematological malignancies and is considered an adverse prognostic factor. In addition, AF1q is expressed in various regions of the brain throughout human neural developmental processes. The expression levels of AF1q and neuron-specific class III β-tubulin (Tuj1), a marker of post-mitotic neurons, are positively correlated in the cerebral cortex. AF1q expression also induces the transformation of human embryonic kidney cells into neurons, indicating that AF1q may play a key role in neuronal differentiation during normal neural development. The activity of AF1q is regulated by RE1-silencing transcription factor (REST), an important regulator of embryonic and neural stem cells during normal development. Furthermore, AF1q is associated with the activity of the Wingless/Integrated (Wnt) signaling pathway, which is critical to normal development of the nervous system. Although the precise role of AF1q is yet to be uncovered, various studies have demonstrated that AF1q is indeed heavily involved in neurodevelopmental processes. The investigation of the role of AF1q in neurodevelopment is important for several reasons. First, it can give a better understanding of the biological and physiological functions of AF1q, a gene that is still poorly understood. Second, it can provide insight into the development of the human nervous system and the complex processes and regulations that are involved. Through the study of AF1q in a neurobiological context, its precise role in neural development may be uncovered, and new therapeutic approaches to neurodevelopmental disorders such as Down syndrome and Alzheimer’s disease may be possible.
5

The IgSF protein MDGA1 regulates morphology during a defined stage of placode-derived neuron maturation in developing chick cranial sensory ganglia

Smith, Alexandra January 2015 (has links)
The developing distal cranial sensory ganglia of the chick present an interesting and tractable model for the study of general processes of neural development. While the early stages of placodal neurogenesis, including induction of the placodes and initiation of the neurogenic programme, have been extensively studied, little is known about the molecular mechanisms that regulate migration of placode-derived neuroblasts and their aggregation to form ganglia. These questions have been addressed in the context of the trigeminal ganglion, however it remains unclear whether these principles apply to the epibranchial ganglia, on which the work presented here is focussed. Molecules potentially involved in controlling placodal neuroblast migration in the epibranchial ganglia were identified through a comparative microarray screen carried out in the Begbie lab. A list of candidate genes implicated in a variety of different cellular was validated by determining expression patterns in the region of the epibranchial CSG by in situ hybridisation. These expression patterns showed that different genes were expressed by different populations within the migratory stream. This question was further addressed through the detailed analysis of the expression patterns of a panel of neuronal and neurogenic markers, leading to the finding that placodal neuroblasts appear to sequentially upregulate different groups of genes as they migrate away from the placode. Neuroblasts within the migratory stream can further be subdivided according to cell morphology, which was assessed through high resolution imaging of GFP-labelled placodal cells. Multipolar and bipolar cells were concentrated around two different regions of the migratory stream with multipolar cells localised near the placode and bipolar cells localised closer to the neural tube. Together these findings support the hypothesis that placodal neuroblasts mature as they migrate towards the site of ganglion aggregation. With this detailed description of the system in mind, the question of molecular control was addressed through the functional characterisation of a candidate gene identified in the original microarray screen. MDGA1, a GPI-anchored IgSF molecule that has been implicated in controlling radial migration of cortical neurons, was specifically expressed in the chick CSG at the relevant stages. RNAi-mediated knockdown and overexpression were used to test the function of MDGA1 in migrating placodal neuroblasts. These experiments showed that MDGA1 negatively regulates the formation and extension of neuronal projections in bipolar neuroblasts. With the mechanisms of MDGA1 function relying entirely on protein-protein interactions at the cell-surface, we then set out to identify and characterise potential MDGA1 binding partners. SPR binding experiments carried out in collaboration with the Aricescu lab revealed that MDGA1 interacts with the Neuroligin family of synaptic proteins. Recent evidence has shown that MDGA1 interacts in cis with NLGN2 in rat hippocampal neurons where it disrupts its interaction in trans with Neurexin1. Neuroligins and Neurexins function to stabilise dendritic filopodia by creating trans-synaptic adhesions and recruiting the synaptic apparatus. Having determined that both NLGN2 and NRXN1 are expressed in placode-derived neuroblasts of the CSG, we propose that these molecules play a role in the stabilisation and extension of neuronal projections in this system and that this function in modulated by MDGA1 function.
6

Neurodevelopmental delay among HIV-infected preschool children receiving antiretroviral therapy and healthy preschool children in Soweto, South Africa

Lowick, Sarah 05 1900 (has links)
Thesis (M.Sc.(Med.))--University of the Witwatersrand, Faculty of Health Sciences, 2012. / Neurodevelopmental delay has been documented in up to 97.5% ofHIV-infected childfen in Soweto who were not yet on ART. With growing numbers of children in South Africa being successfully treated with antiretroviral treatment (ART), the effects of ART on neurocognitive functioning in children require investigation. The objective of this study was to determine the extent of neurodevelopmental delay in stable HIV -infected preschool children (aged) 5-6 years) receiving ART and compare it to an apparently healthy . (unconfirmed HIV-status) group of preschool children. Thirty HIV-infected preschool children (virologically and immunologically stable on ART for> 1 year) were conveniently sampled from 350 eligible children on ART at the Harriet Shezi Children's Clinic in Soweto, Johannesburg. The comparison group comprised thirty well-nourished preschool children attending the Lilian Ngoyi Primary Health Care Clinic in Soweto for routine immunisations. Each child was assessed using the Griffiths Mental Development Scales-Extended Revised Version (GMDS-ER), at a single point in time. The overall developmental z-scores on GMDS-ER were <-2 (indicating severe delay) in 27 (90%) children in the HIV-infected group compared to 23 (76%) in the comparison group (p=0.166). Mental handicap (overall GQ<70) was evident in 46.7% of children in the HIV -infected group compared to 10% in the comparison group (p= 0.002). There was a 7.88-fold increased likelihood of severe delay in the HIV infected group. The HIV -infected group and comparison group had significantly different (p=0.001) mean overall GQ scores of70 (95% CI: 66.0-74.0) and 78 (95% CI: 75.6- 80.5), respectively, with lower mean scores in the HIV -infected group in all individual domains. Early initiation of ART in HIV-infected infants may improve cognitive functioning among this group, however, intervention strategies which optimize early cognitive development for all children in the area, need to be urgently considered.
7

The Structure and Function of the TACC Protein Family in Neurodevelopment

Evans, Matt January 2015 (has links)
Thesis advisor: Laura Anne Lowery / Thesis advisor: Eric Folker / In order to form the exact synaptic connection required for proper neurological function, the growing tip of the neuron hosts an orchestra of hundreds of different proteins interacting with extracellular cues to steer neuron growth in the right direction. The goal of our current research is to study several of the components of this pathway, known as the TACC family. Here, we present a detailed structure/function analysis of the TACC family in regards to binding and activity with other proteins in the growth cone. We investigate the function of TACC3 in mediating neuron outgrowth and guidance in vivo. We have found structural elements of the TACC family that enable their activity. Studying these conserved structures and functions of the TACC family will enable greater understanding of the entire process of cytoskeletal regulation and neurodevelopment. / Thesis (BS) — Boston College, 2015. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Scholar of the College. / Discipline: Biology.
8

Role of Cerebrovascular Abnormalities in the 16p11.2 Deletion Autism Syndrome

Ouellette, Julie 23 January 2019 (has links)
Brain development and function rely on vascular features that ensure adequate supply of oxygen and nutrients from the blood stream. These features consist of a well-established vascular network, a functional blood-brain barrier, as well as cerebral blood flow regulation. Early life impairments in these features can lead to neurodevelopmental defects. Very few studies have considered the contribution of the brain vasculature to autism spectrum disorders (ASD). A recent postmortem study in young ASD brains suggested an impairment in angiogenesis, a process through which new vessels are formed. A possible link between ASD and altered cerebral perfusion has also been suggested by functional imaging studies. Yet, contribution of cerebrovascular deficits to ASD physiopathology remains elusive, hence a detailed analysis of these deficits is needed. ASD are viewed as neurodevelopmental conditions associated with genetic origins. Mutations identified as a possible cause for ASD include the common 16p11.2 deletion, which leads to the haploinsufficiency of approximately 30 highly-conserved genes. In this thesis, we are using a multidisciplinary approach in order to decipher the cerebrovascular underpinnings of ASD in a mouse model of the 16p11.2 deletion syndrome (16p11.2df/+ mice). We have identified functional and structural cerebrovascular deficits during postnatal development in constitutive 16p11.2df/+ mutants. In particular, 16p11.2df/+ mice display a significant decrease in microvascular branching and density in the cerebral cortex at P14 when compared to age-matched WT littermates. In addition, 16p11.2df/+ mice display a collection of functional abnormalities at P50 when compared to WT mice, such as altered neurovascular coupling in vivo and altered vascular reactivity ex vivo. Notably, we demonstrated a defective endothelium-dependent vasodilation in 16p11.2df/+ mice, while smooth muscle function is unaffected. Furthermore, we generated mice harboring the endothelial-specific 16p11.2 haploinsufficiency (Cdh5-Cretg/+;16p11.2flox/+) in order to dissect the endothelial contribution to ASD phenotypes. These mice underwent behavioral testing to assess whether they display 16p11.2 syndrome -related characteristics. We demonstrated that these conditional mutant mice show home cage hyperactivity in the beam break test, repetitive behaviors in the marble burying test, as well as motor coordination deficits in the rotarod test. Our findings thus establish endothelial cells as key contributors to the pathophysiology of the 16p11.2 deletion syndrome, and provide novel insight into how the cerebral endothelium fine-tunes brain maturation.
9

Insights into neurodevelopmental disorders: molecular and behavioral studies using the zebrafish

Fuller, Tyson David 01 August 2019 (has links)
Neurodevelopmental disorders (ND) present a significant burden on society as over 5% of the US population is diagnosed with a ND. While environmental and biological factors have been associated with some cases of NDs, many still have unknown etiology. Strong comorbidities of NDs have been shown suggesting common biological processes of disease development. Sequencing technologies have allowed for the unprecedented identification of new candidate genes associated with NDs and many genes have been linked to multiple NDs. Developing robust methods to functionally validate these candidates is a critical next step for aiding patients with NDs. Using the zebrafish (Danio rerio), we characterized the developmental requirement of epilepsy candidate genes in the context of gene knockdown (KD). We demonstrated three different larval responses to pentylenetetrazol (PTZ) (hyperactive, hypoactive, or the same as control). We characterized the two genes resulting in a hyperactive response, Zinc Finger Homeobox 3 (ZFHX3) and Spectrin Repeat Domain Containing Nuclear Envelope Protein 1 (SYNE1), in greater detail. ZFHX3 is expressed in distinct brain regions during development and shows strong expression along nerve fiber tracts. SYNE1 shows broad expression during development that is enriched in the brain. Using CRISPR/Cas9 we generated a predicted null SYNE1 allele and recapitulated the seizure sensitivity phenotype in mutant larvae. Using a 60-hour behavioral assay we also demonstrate a generalized daytime hyperactivity in SYNE1 mutants. Our studies confirm ZFHX3 and SYNE1 as strong candidates for further study in epilepsy and suggest a role for SYNE1 in multiple NDs such as autism and attention-deficit/hyperactivity disorder.
10

Unique roles for the C3 gamma-protocadherin isoform in WNT signaling and dendrite arborization

Mah, Kar Men 01 December 2017 (has links)
A key component of neural circuit formation is the elaboration of complex dendritic arbors, the pattern of which constrains inputs to the neuron and thus, the information it processes. As such, many neurodevelopmental disorders such as autism and Down, Rett, and Fragile X Syndromes are associated with reduced forebrain dendrite arborization. Identifying molecules involved in regulating dendrite arborization and neural circuitry formation therefore, is a start to understanding these disorders. Nearly 70 cadherin superfamily adhesion molecules are encoded by the Pcdha, Pcdhb, and Pcdhg gene clusters. These so-called clustered protocadherins (Pcdhs) are broadly expressed throughout the nervous system, with lower levels found in a few non-neuronal tissues. Each neuron expresses a limited repertoire of clustered Pcdh genes, a complicated process controlled by differential methylation and promoter choice. The clustered Pcdh proteins interact homophilically in trans as cis-multimers, which has the potential to generate a combinatorially explosive number of distinct adhesive interfaces that may give neurons unique molecular identities important for circuit formation. Functional studies of animals in which clustered Pcdhs have been deleted or disrupted demonstrate that these proteins play critical roles in neuronal survival, axon and dendrite arborization, and synaptogenesis. Additionally, they have been implicated in the progression of several cancers, suggesting that basic studies of their function and signaling pathways will have important future clinical applications. Recent work has shown that γ-Pcdhs can regulate the Wnt signaling pathway, a common tumorigenic pathway which also play roles in neurodevelopment, but the molecular mechanisms remain unknown. I determined that γ-Pcdhs differentially regulate Wnt signaling: the C3 isoform uniquely inhibits the pathway while 13 other isoforms upregulate Wnt signaling. Focusing on γ-Pcdh-C3, I show that the variable cytoplasmic domain (VCD) is critical for Wnt signaling inhibition. γ-Pcdh-C3, but not other isoforms, physically interacts with Axin1, a key component of the canonical Wnt pathway. The C3 VCD competes with Dishevelled for binding to the DIX domain of Axin1, which stabilizes Axin1 at the membrane and leads to reduced phosphorylation of Wnt co-receptor Lrp6. I also present evidence that the Wnt pathway can be modulated up (by γ-Pcdh-A1) or down (by γ-Pcdh-C3) in the cerebral cortex in vivo, using conditional transgenic alleles. Studies have implicated γ-Pcdhs as a whole, in many neurodevelopmental processes but little is known if distinct roles exists for individual isoforms. By using a specific C3-isoform knockout mouse line engineered in collaboration with Dr. Robert Burgess of The Jackson Laboratory, I was able to uncover a unique role for the C3-isoform in the regulation of dendrite arborization. Mice without γ-Pcdh-C3 exhibit significantly reduced dendrite complexity in cortical neurons. This phenotype was recapitulated in cultured cortical neurons in vitro, which can be rescued by reintroducing the C3-isoform. The ability of γ-Pcdh-C3 to promote dendrite arborization cell-autonomously was abrogated when Axin1 was depleted with an shRNA, indicating that this process by which γ-Pcdh-C3 regulates dendrite arborization is mediated by its interaction with Axin1, which I had previously demonstrated. Together, these data suggest that γ-Pcdh-C3 has unique roles distinct from other γ-Pcdhs, in the regulation of Wnt signaling and dendrite arborization, both of which are mediated by interaction with Axin1.

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