Contribution of Ref(2)p to regulation of Drosophila notum epithelial cell apico-basal polarity and phenotype

Cell polarity impacts on the maintenance of cell shape, cell-cell junction integrity, and protrusions formation and dynamics. Further, polarity regulates cell movement, proliferation and differentiation. Conversely when cells lose their polarity they may be susceptible to dysfunction that may underlie degenerative disorders and tumour progression. Cell polarity and polarity protein complexes are highly conserved between different organisms from unicellular to multicellular, and from invertebrates to vertebrates. The focus of this study is the apico-basal polarity that is established normally in epithelial cells. The protein p62 has been revealed to have a role in epithelial cells phenotypic alteration. It is considered as a multifunctional scaffold protein and acts as a signalling hub for different pathways, and through interactions with the polarity protein aPKC we hypothesise that it may regulate apico-basal polarity. Ref(2)p is the Drosophila homologue of p62 and using Drosophila melanogaster as a model system we investigated the effects of Ref(2)p mutation or overexpression on epithelial cell apico-basal polarity, cell shape and protrusion dynamics. Our data suggests that Ref(2)p is required to maintain normal cell size, cell-cell junction stability, and protrusion dynamics and formation. Both the PB1 and UBA domains of Ref(2)p were recognized to be essential for localizing aPKC apically. As a multifunctional protein, Ref(2)p showed a further role in cell division, chromosome segregation and tumour repression. Ref(2)p mutants, as well as aPKC mutants, showed a decrease in cell division rate and phenocopied a blebbing phenotype detected in SCAR mutant dividing cells. Mechanistically, these phenotypes are likely at least due to Ref(2)p’s interaction with aPKC and on broader scale due to changes in Ref(2)p mediated autophagy on polarity proteins. Since levels of autophagic activity, mediated by Ref(2)p, have potential effects on polarity proteins levels, which affect apico-basal polarity, cell size and actin cytoskeleton organization

Contribution of Ref(2)p to regulation of Drosophila notum epithelial cell apico-basal polarity and phenotype

Cell polarity impacts on the maintenance of cell shape, cell-cell junction integrity, and protrusion formation and dynamics. Further, polarity additionally regulates cell movement, proliferation and differentiation. Conversely when cells lose their polarity they may be susceptible to dysfunction that may underlie degenerative disorders. Cell polarity and polarity protein complexes are highly conserved between different organisms from unicellular to multi-cellular, and from invertebrates to vertebrates. The focus of this study is the apico-basal polarity that is established normally in epithelial cells. p62 is a multifunctional scaffold protein which acts as a signalling hub for different pathways, and through interactions with the polarity protein aPKC we hypothesise that it may regulate apico-basal polarity. Ref(2)p is the Drosophila homologue of p62 and using Drosophila as a model system we are investigating the effects of Ref(2)p mutation or expression levels on apico-basal polarity, cell shape and protrusion dynamics in the epithelial cells of the dorsal thorax. Our preliminary data suggest that Ref(2)p is required to maintain normal cell size, cell-cell junctions and protrusion dynamics. Mechanistically, these phenotypes may be due to Ref(2)p’s interaction with polarity proteins or broader changes in Ref(2)p-mediated autophagy

Glial-Specific Functions of Microcephaly Protein WDR62 and Interaction with the Mitotic Kinase AURKA Are Essential for Drosophila Brain Growth

The second most commonly mutated gene in primary microcephaly (MCPH) patients is wd40-repeat protein 62 (wdr62), but the relative contribution of WDR62 function to the growth of major brain lineages is unknown. Here, we use Drosophila models to dissect lineagespecific WDR62 function(s). Interestingly, although neural stem cell (neuroblast)-specific depletion of WDR62 significantly decreased neuroblast number, brain size was unchanged. In contrast, glial lineage-specific WDR62 depletion significantly decreased brain volume. Moreover, loss of function in glia not only decreased the glial population but also non-autonomously caused neuroblast loss.We further demonstrated that WDR62 controls brain growth through lineage-specific interactions with master mitotic signaling kinase, AURKA. Depletion of AURKA in neuroblasts drives brain overgrowth, which was suppressed by WDR62 co-depletion. In contrast, glial-specific depletion of AURKA significantly decreased brain volume, which was further decreased by WDR62 co-depletion. Thus, dissecting relative contributions of MCPH factors to individual neural lineages will be critical for understanding complex diseases such as microcephaly

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Contribution of Ref(2)p to regulation of Drosophila notum epithelial cell apico-basal polarity and phenotype

Cell polarity impacts on the maintenance of cell shape, cell-cell junction integrity, and protrusions formation and dynamics. Further, polarity regulates cell movement, proliferation and differentiation. Conversely when cells lose their polarity they may be susceptible to dysfunction that may underlie degenerative disorders and tumour progression. Cell polarity and polarity protein complexes are highly conserved between different organisms from unicellular to multicellular, and from invertebrates to vertebrates. The focus of this study is the apico-basal polarity that is established normally in epithelial cells. The protein p62 has been revealed to have a role in epithelial cells phenotypic alteration. It is considered as a multifunctional scaffold protein and acts as a signalling hub for different pathways, and through interactions with the polarity protein aPKC we hypothesise that it may regulate apico-basal polarity. Ref(2)p is the Drosophila homologue of p62 and using Drosophila melanogaster as a model system we investigated the effects of Ref(2)p mutation or overexpression on epithelial cell apico-basal polarity, cell shape and protrusion dynamics. Our data suggests that Ref(2)p is required to maintain normal cell size, cell-cell junction stability, and protrusion dynamics and formation. Both the PB1 and UBA domains of Ref(2)p were recognized to be essential for localizing aPKC apically. As a multifunctional protein, Ref(2)p showed a further role in cell division, chromosome segregation and tumour repression. Ref(2)p mutants, as well as aPKC mutants, showed a decrease in cell division rate and phenocopied a blebbing phenotype detected in SCAR mutant dividing cells. Mechanistically, these phenotypes are likely at least due to Ref(2)p’s interaction with aPKC and on broader scale due to changes in Ref(2)p mediated autophagy on polarity proteins. Since levels of autophagic activity, mediated by Ref(2)p, have potential effects on polarity proteins levels, which affect apico-basal polarity, cell size and actin cytoskeleton organization

Factors that influence adult neurogenesis as potential therapy

Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain. This phenomenon was first described over 50 years ago and it is now firmly established that new neurons are continually generated in distinct regions of the adult brain. The potential of enhancing the neurogenic process lies in improved brain cognition and neuronal plasticity particularly in the context of neuronal injury and neurodegenerative disorders. In addition, adult neurogenesis might also play a role in mood and affective disorders. The factors that regulate adult neurogenesis have been broadly studied. However, the underlying molecular mechanisms of regulating neurogenesis are still not fully defined. In this review, we will provide critical analysis of our current understanding of the factors and molecular mechanisms that determine neurogenesis. We will further discuss pre-clinical and clinical studies that have investigated the potential of modulating neurogenesis as therapeutic intervention in neurodegeneration

Elevated levels of Drosophila Wdr62 promote glial cell growth and proliferation through AURKA signalling to AKT and MYC

WD40-Repeat Protein 62 (WDR62) is required to maintain neural and glial cell populations during embryonic brain growth. Although elevated expression of WDR62 is frequently associated with several tumour types, potential effects of excess WDR62 on proliferative growth remain undefined. Here, we demonstrate that glia specific overexpression of WDR62 in Drosophila larval brains resulted in increased cell size, over-proliferation and increased brain volume, without overt disruption of tissue organization. We further demonstrate WDR62 promoted over-proliferation and brain overgrowth by activating AURKA and pAKT signalling to increase MYC function in glial cells. Together these data suggest WDR62 normally functions in the glial lineage to activate oncogenic signalling networks, promoting proliferation and brain overgrowth

The spindle-associated microcephaly protein, WDR62, is required for neurogenesis and development of the hippocampus

Primary microcephaly genes (MCPH) are required for the embryonic expansion of the mammalian cerebral cortex. However,\ua0MCPH\ua0mutations may spare growth in other regions of the developing forebrain which reinforces context-dependent functions for distinct\ua0MCPH\ua0genes in neurodevelopment. Mutations in the\ua0MCPH2\ua0gene,\ua0WD40-repeat protein 62\ua0(WDR62), are causative of primary microcephaly and cortical malformations in humans. WDR62 is a spindle microtubule-associated phosphoprotein that is required for timely and oriented cell divisions. Recent studies in rodent models confirm that WDR62 loss or mutation causes thinning of the neocortex and disrupted proliferation of apical progenitors reinforcing critical requirements in the maintenance of radial glia. However, potential contributions for WDR62 in hippocampal development had not been previously defined. Using CRISPR/Cas9 gene editing, we generated mouse models with patient-derived non-synonymous missense mutations (WDR62V66M\ua0and WDR62R439H) and a null mutation (herein referred to as WDR62Stop) for comparison. We find that WDR62 deletion or mutation resulted in a significant reduction in the thickness of the hippocampal ventricular zone and the area of the dentate gyrus (DG). This was associated with the mitotic arrest and depletion of radial glia and intermediate progenitors in the ammonic neuroepithelium. As a consequence, we find that the number of mitotic dentate precursors in the migratory stream and granule neurons in the DG was reduced with WDR62 mutation. These findings reveal that WDR62 is required for neurogenesis and the growth of the hippocampus during embryonic development

The Role of WD40-Repeat Protein 62 (MCPH2) in Brain Growth: Diverse Molecular and Cellular Mechanisms Required for Cortical Development

Genetic disruptions of spindle/centrosomeassociated WD40-repeat protein 62 (WDR62) are causative for autosomal recessive primary microcephaly (MCPH) and a broader range of cortical malformations. Since the identification of WDR62 as encoded by the MCPH2 locus in 2010, recent studies that have deleted/depleted WDR62 in various animal models of cortical development have highlighted conserved functions in brain growth. Here, we provide a timely review of our current understanding of WDR62 contributions in the self-renewal, expansion and fate specification of neural stem and progenitor cells that are critical for neocortical development. Recent studies have revealed multiple functions for WDR62 in the regulation of spindle organization, mitotic progression and the duplication and biased inheritance of centrosomes during asymmetric divisions. We also discuss recently elaborated WDR62 interaction partners that include Aurora and c-Jun N-terminal kinases as part of complex signalling mechanisms that may define its neural functions. These studies provide new insights into the molecular and cellular processes that are required for brain formation and implicated in the genesis of primary microcephaly.DN acknowledges funding support from the National Health and Medical Research Council (APP1046032), Australian Research Council (FT120100193) and Cancer Council (APP1101931). NL was a recipient of a Melbourne International Research Scholarship from the University of Melbourne and BS is a recipient of a UQ International Scholarship from the University of Queensland