LIV Well when Life Is Limited: Technology to Support Independence at Home.

There has been significant growth in technologies and services creating 'care at home' ecosystems for people with life-limiting conditions such as dementia. Dementia is one of the leading causes of disability and loss of independence that causes a heavy burden for families and caregivers. There is a clear need to support independent living of people living with dementia and their caregivers. Health technologies can help to foster supported living and social connection. The LIV app, developed by Miroma Project Factory and piloted in collaboration with CSIRO, was designed to achieve these aims. Here we describe the development and functionality of the app and present the preliminary findings from the pilot trial.

Sensing Swelling: Towards Remote Monitoring of Craniectomy Patients.

Decompressive craniectomy (DC) is a surgical procedure where a portion of the skull is removed to relieve potentially fatal brain swelling. As the swelling can take months to subside, the patient is discharged from an acute care facility to recover prior to cranioplasty (reconstruction surgery). Cranioplasty is associated with complications due to infection, seizure, haematoma and death. The interval between these surgeries is potentially a modifiable risk factor to reduce the rate of complication. We aim to allow clinicians to remotely monitor patients to facilitate an optimal pre-operative review. We have developed a platform technology encompassing a 'smart' device fitted into a skullcap to measure physiological parameters, such as changes in brain swelling, and a clinician portal that allows remote viewing of the patients' physiological data. The use of patient generated data during the transition between craniectomy and cranioplasty has the potential to significantly improve neurorehabilitation outcomes for patients.

A New Role for Chatbots: Automation of a Sleep-Dependent Memory Task.

Sleep is known to contribute to memory consolidation. Sleep-dependent memory is not often studied in patients with mild cognitive impairment (MCI), however, due to the need to attend sleep laboratories which are typically expensive, time-consuming and lacking in trained task administrators. We developed a conversation agent able to deliver a sleep-dependent memory task at home. Utility of the chatbot was confirmed through in-house testing and focus groups. The chatbot promises consistent task delivery and improved access for people with MCI.

Spread of stinging ants to oceanic islands, and the need to raise awareness of prevention and treatment of ant stings.

OBJECTIVE: Venomous invasive ants are rapidly dispersing throughout oceanic islands. Medics unfamiliar with envenomation or venom-induced anaphylaxis may be unprepared for the range of possible reactions and corresponding treatments. We detail the suboptimal treatment of a patient suffering anaphylaxis from an ant sting on a remote island and describe what treatment should have been provided. METHODS: The patient experienced stings on his feet from an ant later identified as tropical fire ant, Solenopsis geminata. Clinical examination revealed throat swelling without obstruction of the airway or pharynx. RESULTS: The patient was provided the following suboptimal treatment: intravenously-administered antihistamine and saline perfusion. Injected epinephrine should be the standard first line of treatment for anaphylaxis, even when not all symptoms are present. CONCLUSION: A rise in invasive hymenopteran stings on oceanic islands is inevitable, and proactively improving public awareness and medical training could save lives.

Early brain morphometrics from neonatal MRI predict motor and cognitive outcomes at 2-years corrected age in very preterm infants.

Infants born very preterm face a range of neurodevelopmental challenges in cognitive, language, behavioural and/or motor domains. Early accurate identification of those at risk of adverse neurodevelopmental outcomes, through clinical assessment and Magnetic Resonance Imaging (MRI), enables prognostication of outcomes and the initiation of targeted early interventions. This study utilises a prospective cohort of 181 infants born <31 weeks gestation, who had 3T MRIs acquired at 29-35 weeks postmenstrual age and a comprehensive neurodevelopmental evaluation at 2 years corrected age (CA). Cognitive, language and motor outcomes were assessed using the Bayley Scales of Infant and Toddler Development - Third Edition and functional motor outcomes using the Neuro-sensory Motor Developmental Assessment. By leveraging advanced structural MRI pre-processing steps to standardise the data, and the state-of-the-art developing Human Connectome Pipeline, early MRI biomarkers of neurodevelopmental outcomes were identified. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, significant associations between brain structure on early MRIs with 2-year outcomes were obtained (r = 0.51 and 0.48 for motor and cognitive outcomes respectively) on an independent 25% of the data. Additionally, important brain biomarkers from early MRIs were identified, including cortical grey matter volumes, as well as cortical thickness and sulcal depth across the entire cortex. Adverse outcome on the Bayley-III motor and cognitive composite scores were accurately predicted, with an Area Under the Curve of 0.86 for both scores. These associations between 2-year outcomes and patient prognosis and early neonatal MRI measures demonstrate the utility of imaging prior to term equivalent age for providing earlier commencement of targeted interventions for infants born preterm.

Socially-Assistive Robots to Support Learning in Students on the Autism Spectrum: Investigating Educator Perspectives and a Pilot Trial of a Mobile Platform to Remove Barriers to Implementation.

Technology offers educators tools that can tailor learning to students' learning styles and interests. Research into the use of socially-assistive robots as a learning support for children on the autism spectrum are showing promising results. However, to date, few schools have introduced these robots to support learning in students on the autism spectrum. This paper reports on a research project that investigated the barriers to implementing socially-assistive robot supported learning, and the expectations, perceived benefits and concerns of school teachers and therapists of students on the autism spectrum and adults on the autism spectrum. First, three focus groups were conducted with six adults on the autism spectrum, and 13 teachers and therapists of students from two autism-specific schools. During the focus groups, there was cautious optimism from participants about the value of socially-assistive robots for teaching support. While the data showed that participants were in favour of trialling socially-assistive robots in the classroom, they also raised several concerns and potential barriers to implementation, including the need for teacher training. In response to their concerns, the second part of the project focussed on developing a software platform and mobile application (app) to support the introduction of robots into autism-specific classrooms. The software platform and app were then trialled in two schools (n = 7 teachers and therapists). Results from focus groups indicated that participants believe socially-assistive robots could be useful for learning support, as the mobile app provides an easy to use tool to support preparing and conducting lessons that would motivate them to trial robots in the classroom.

Impaired spatial memory in adult vitamin D deficient BALB/c mice is associated with reductions in spine density, nitric oxide, and neural nitric oxide synthase in the hippocampus.

Vitamin D deficiency is prevalent in adults and is associated with cognitive impairment. However, the mechanism by which adult vitamin D (AVD) deficiency affects cognitive function remains unclear. We examined spatial memory impairment in AVD-deficient BALB/c mice and its underlying mechanism by measuring spine density, long term potentiation (LTP), nitric oxide (NO), neuronal nitric oxide synthase (nNOS), and endothelial NOS (eNOS) in the hippocampus. Adult male BALB/c mice were fed a control or vitamin D deficient diet for 20 weeks. Spatial memory performance was measured using an active place avoidance (APA) task, where AVD-deficient mice had reduced latency entering the shock zone compared to controls. We characterised hippocampal spine morphology in the CA1 and dentate gyrus (DG) and made electrophysiological recordings in the hippocampus of behaviourally naïve mice to measure LTP. We next measured NO, as well as glutathione, lipid peroxidation and oxidation of protein products and quantified hippocampal immunoreactivity for nNOS and eNOS. Spine morphology analysis revealed a significant reduction in the number of mushroom spines in the CA1 dendrites but not in the DG. There was no effect of diet on LTP. However, hippocampal NO levels were depleted whereas other oxidation markers were unaltered by AVD deficiency. We also showed a reduced nNOS, but not eNOS, immunoreactivity. Finally, vitamin D supplementation for 10 weeks to AVD-deficient mice restored nNOS immunoreactivity to that seen in in control mice. Our results suggest that lower levels of NO and reduced nNOS immunostaining contribute to hippocampal-dependent spatial learning deficits in AVD-deficient mice.

A validation study of a ballistocardiograph sleep tracker against polysomnography.

STUDY OBJECTIVES: Consumer home sleep trackers provide a great opportunity for longitudinal objective sleep monitoring. Nonwearable sleep devices cause little to no disruption in the daily life routine and need little maintenance. However, their validity needs further investigation. This study aims to evaluate the accuracy of sleep outcomes of EMFIT Quantified Sleep (QS), an unobtrusive nonwearable sleep tracker based on ballistocardiography, against polysomnography. METHODS: 62 sleep-lab patients underwent a single clinical polysomnography with measures simultaneously collected through polysomnography and EMFIT QS. Resting heart rate, total sleep time, wake after sleep onset, sleep onset latency, and duration in sleep stages, collected from the 2 devices, were compared using paired t-tests and their agreement analyzed using Bland-Altman plots. Additionally, continuous heart rate and sleep stages in 30-seconds epochs were evaluated. RESULTS: EMFIT QS data loss occurred in 47% of participants. In the remaining 33 participants (15 women, with mean age of 53.7 ± 16.5 years), EMFIT QS overestimated total sleep time by 177.5 ± 119.4 minutes (p<0.001) and underestimated wake after sleep onset by 44.74 ± 68.81 minutes (P < .001). It accurately measured average resting heart rate and was able to distinguish sleep onset latency with some accuracy. However, the agreement between EMFIT QS and polysomnography on sleep-wake detection was low (kappa = 0.13, P < .001), EMFIT QS failed to distinguish sleep stages. CONCLUSIONS: A consensus between polysomnography and EMFIT QS was found in sleep onset latency and average heart rate. There was significant discrepancy and lack of consensus in other sleep outcomes. These findings indicated that further development is necessary before using EMFIT QS in clinical and research settings. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Sleep parameter validation of a consumer home sleep monitoring device, EMFIT Quantified Sleep (QS), against Polysomnography; URL: https://www.anzctr.org.au/ACTRN12621000600842.aspx; Identifier: ACTRN12621000600842. CITATION: Kholghi M, Szollosi I, Hollamby M, Bradford D, Zhang Q. A validation study of a ballistocardiograph sleep tracker against polysomnography. J Clin Sleep Med. 2022;18(4):1203-1210.

Enabling Nurse-Patient Communication With a Mobile App: Controlled Pretest-Posttest Study With Nurses and Non-English-Speaking Patients.

BACKGROUND: There is growing concern regarding the implications of miscommunication in health care settings, the results of which can have serious detrimental impacts on patient safety and health outcomes. Effective communication between nurses and patients is integral in the delivery of timely, competent, and safe care. In a hospital environment where care is delivered 24 hours a day, interpreters are not always available. In 2014, we developed a communication app to support patients' interactions with allied health clinicians when interpreters are not present. In 2017, we expanded this app to meet the needs of the nursing workforce. The app contains a fixed set of phrases translated into common languages, and communication is supported by text, images, audio content, and video content. OBJECTIVE: This study aims to evaluate the efficacy of the communication app to support nursing staff during the provision of standard care to patients from non-English-speaking backgrounds when an interpreter is not available. METHODS: This study used a one-group pretest-posttest sequential explanatory mixed methods research design, with quantitative data analyzed using inferential statistics and qualitative data analyzed via thematic content analysis. A total of 134 observation sessions (82 pretest and 52 posttest) of everyday nurse-patient interactions and 396 app use sessions were recorded. In addition, a total of 134 surveys (82 pretest and 52 posttest) with nursing staff, 7 interviews with patients, and 3 focus groups with a total of 9 nursing staff participants were held between January and November 2017. RESULTS: In the absence of the app, baseline interactions with patients from English-speaking backgrounds were rated as more successful (t80=5.69; P<.001) than interactions with patients from non-English-speaking backgrounds. When staff used the app during the live trial, interactions with patients from non-English-speaking backgrounds were rated as more successful than interactions without the app (F2,119=8.17; P<.001; η2=0.37). In addition, the level of staff frustration was rated lower when the app was used to communicate (t80=2.71; P=.008; r=0.29). Most participants indicated that the app assisted them in communicating. CONCLUSIONS: Through the use of the app, a number of patients from non-English-speaking backgrounds experienced better provision of standard care, similar to their English-speaking peers. Thus, the app can be seen as contributing to the delivery of equitable health care.

Introducing Edna: A trainee chatbot designed to support communication about additional (secondary) genomic findings.

OBJECTIVE: To support informed decision-making about reanalysis of clinical genomic data for risk of preventable conditions ('additional findings') by developing a chatbot (electronic genetic resource, 'eDNA'). METHODS: Interactions in pre-test genetic counseling sessions (13.5 h) about additional findings were characterized using proponent, thematic and semantic analyses of transcripts. We then wrote interfaces to draw supplementary data from external genetics applications. To create Edna, this content was programmed using a chatbot framework which interacts with patients via speech-to-text. RESULTS: Conditions, terms, explanations of concepts, and key factors to consider in decision making were all encoded into chatbot conversations emulating counseling session flows. Patient agency can be enhanced by prompted consideration of the personal and familial implications of testing. Similarly, health literacy can be broadened through explanation of genetic conditions and terminology. Novel aspects include sentiment analysis and collection of family history. Medical advice and the impact of existing genetic conditions were deemed inappropriate for inclusion. CONCLUSION: Edna's successful development represents a movement towards accessible, acceptable and well-supported digital health processes for patients to make informed decisions for additional findings. PRACTICE IMPLICATIONS: Edna complements genetic counseling by collecting and providing genomic information before or after pre-test consultations.

Predicting motor outcome in preterm infants from very early brain diffusion MRI using a deep learning convolutional neural network (CNN) model.

BACKGROUND AND AIMS: Preterm birth imposes a high risk for developing neuromotor delay. Earlier prediction of adverse outcome in preterm infants is crucial for referral to earlier intervention. This study aimed to predict abnormal motor outcome at 2 years from early brain diffusion magnetic resonance imaging (MRI) acquired between 29 and 35 weeks postmenstrual age (PMA) using a deep learning convolutional neural network (CNN) model. METHODS: Seventy-seven very preterm infants (born <31 weeks gestational age (GA)) in a prospective longitudinal cohort underwent diffusion MR imaging (3T Siemens Trio; 64 directions, b â€‹= â€‹2000 â€‹s/mm2). Motor outcome at 2 years corrected age (CA) was measured by Neuro-Sensory Motor Developmental Assessment (NSMDA). Scores were dichotomised into normal (functional score: 0, normal; n â€‹= â€‹48) and abnormal scores (functional score: 1-5, mild-profound; n â€‹= â€‹29). MRIs were pre-processed to reduce artefacts, upsampled to 1.25 â€‹mm isotropic resolution and maps of fractional anisotropy (FA) were estimated. Patches extracted from each image were used as inputs to train a CNN, wherein each image patch predicted either normal or abnormal outcome. In a postprocessing step, an image was classified as predicting abnormal outcome if at least 27% (determined by a grid search to maximise the model performance) of its patches predicted abnormal outcome. Otherwise, it was considered as normal. Ten-fold cross-validation was used to estimate performance. Finally, heatmaps of model predictions for patches in abnormal scans were generated to explore the locations associated with abnormal outcome. RESULTS: For the identification of infants with abnormal motor outcome based on the FA data from early MRI, we achieved mean sensitivity 70% (standard deviation SD 19%), mean specificity 74% (SD 39%), mean AUC (area under the receiver operating characteristic curve) 72% (SD 14%), mean F1 score of 68% (SD 13%) and mean accuracy 73% (SD 19%) on an unseen test data set. Patch-based prediction heatmaps showed that the patches around the motor cortex and somatosensory regions were most frequently identified by the model with high precision (74%) as a location associated with abnormal outcome. Part of the cerebellum, and occipital and frontal lobes were also highly associated with abnormal NSMDA/motor outcome. DISCUSSION/CONCLUSION: This study established the potential of an early brain MRI-based deep learning CNN model to identify preterm infants at risk of a later motor impairment and to identify brain regions predictive of adverse outcome. Results suggest that predictions can be made from FA maps of diffusion MRIs well before term equivalent age (TEA) without any prior knowledge of which MRI features to extract and associated feature extraction steps. This method, therefore, is suitable for any case of brain condition/abnormality. Future studies should be conducted on a larger cohort to re-validate the robustness and effectiveness of these models.

Vitamin D deficiency is associated with reduced hippocampal volume and disrupted structural connectivity in patients with mild cognitive impairment.

Vitamin D deficiency may exacerbate adverse neurocognitive outcomes in the progression of diseases such as Parkinson's, Alzheimer's, and other dementias. Mild cognitive impairment (MCI) is prodromal for these neurocognitive disorders and neuroimaging studies suggest that, in the elderly, this cognitive impairment is associated with a reduction in hippocampal volume and white matter structural integrity. To test whether vitamin D is associated with neuroanatomical correlates of MCI, we analyzed an existing structural and diffusion MRI dataset of elderly patients with MCI. Based on serum 25-OHD levels, patients were categorized into serum 25-OHD deficient (<12 ng/mL, n = 27) or not-deficient (>12 ng/mL, n = 29). Freesurfer 6.0 was used to parcellate the whole brain into 164 structures and segment the hippocampal subfields. Whole-brain structural connectomes were generated using probabilistic tractography with MRtrix. The network-based statistic (NBS) was used to identify subnetworks of connections that significantly differed between the groups. We found a significant reduction in total hippocampal volume in the serum 25-OHD deficient group especially in the CA1, molecular layer, dentate gyrus, and fimbria. We observed a connection deficit in 13 regions with the right hippocampus at the center of the disrupted network. Our results demonstrate that low vitamin D is associated with reduced volumes of hippocampal subfields and connection deficits in elderly people with MCI, which may exacerbate neurocognitive outcomes. Longitudinal studies are now required to determine if vitamin D can serve as a biomarker for Alzheimer's disease and if intervention can prevent the progression from MCI to major cognitive disorders.

CALD Assist-Nursing: Improving communication in the absence of interpreters.

AIMS AND OBJECTIVES: To develop a communication app to support nursing staff during the provision of standard care of patients from non-English-speaking backgrounds (NESBs), when an interpreter is not available. This paper reports on the user needs analysis phase that informed the development, content and functionality of the app. BACKGROUND: In 2014 we developed CALD Assist, a communication app to support patient interactions with allied health clinicians when interpreters are not present. It includes 95 commonly used phrases professionally interpreted into 10 languages and grouped by discipline. This work expands upon our previous app to meet the needs of the nursing workforce. DESIGN: Qualitative through focus groups, observations and interviews, with a quantitative component from observational data and staff surveys. METHODS: Four focus groups with hospital staff, ten interviews with patients from NESBs and 85 observation sessions of everyday patient-staff interactions followed by staff surveys (n = 85) were held between January and June 2017. RESULTS: Baseline data prior to app development revealed that staff confidence of the patients' level of understanding and the success of the interaction were significantly greater for English-speaking (ES) patients, than for non-English-speaking patients. A total of 143 phrases were identified and subdivided into 16 categories for inclusion in the new app. CONCLUSION: Staff participants highlighted that patients from NESBs are a challenging patient group to interact with. Patient and staff participants identified a range of areas where the nursing app could benefit, including pain management, mobility, hygiene and nutrition. RELEVANCE TO CLINICAL PRACTICE: The proposed app can be used to reduce variances in practice and provide a timely and positive patient experience for patients from NESBs who are unable to communicate in English during hospital admissions.

Behavioural Effects of Adult Vitamin D Deficiency in BALB/c Mice Are not Associated with Proliferation or Survival of Neurons in the Adult Hippocampus.

Epidemiological studies have shown that up to one third of adults have insufficient levels of vitamin D and there is an association between low vitamin D concentrations and adverse brain outcomes, such as depression. Vitamin D has been shown to be involved in processes associated with neurogenesis during development. Therefore, the aim of this study was to test the hypothesis that adult vitamin D (AVD) deficiency in BALB/c mice was associated with (a) adult hippocampal neurogenesis at baseline, b) following 6 weeks of voluntary wheel running and (c) a depressive-like phenotype on the forced swim test (FST), which may be linked to alterations in hippocampal neurogenesis. We assessed proliferation and survival of adult born hippocampal neurons by counting the number of cells positive for Ki67 and doublecortin (DCX), and incorporation of 5-Bromo-2'-Deoxyuridine (BrdU) within newly born mature neurons using immunohistochemistry. There were no significant effects of diet on number of Ki67+, DCX+ or BrdU+ cells in the dentate gyrus. All mice showed significantly increased number of Ki67+ cells and BrdU incorporation, and decreased immobility time in the FST, after voluntary wheel running. A significant correlation was found in control mice between immobility time in the FST and level of hippocampal neurogenesis, however, no such correlation was found for AVD-deficient mice. We conclude that AVD deficiency was not associated with impaired proliferation or survival of adult born neurons in BALB/c mice and that the impact on rodent behaviour may not be due to altered neurogenesis per se, but to altered function of new hippocampal neurons or processes independent of adult neurogenesis.

Making an APPropriate Care Program for Indigenous Cardiac Disease: Customization of an Existing Cardiac Rehabilitation Program.

Cardiovascular disease is a major health problem for all Australians and is the leading cause of death in Aboriginal and Torres Strait Islanders. In 2010, more then 50% of all heart attack deaths were due to repeated events. Cardiac rehabilitation programs have been proven to be effective in preventing the recurrence of cardiac events and readmission to hospitals. There are however, many barriers to the use of these programs. To address these barriers, CSIRO developed an IT enabled cardiac rehabilitation program delivered by mobile phone through a smartphone app and succesfully trialed it in an urban general population. If these results can be replicated in Indigenous populations, the program has the potential to significantly improve life expectancy and help close the gap in health outcomes. The challenge described in this paper is customizing the existing cardiac health program to make it culturally relevant and suitable for Indigenous Australians living in urban and remote communities.

The Netrin/RGM receptor, Neogenin, controls adult neurogenesis by promoting neuroblast migration and cell cycle exit.

A comprehensive understanding of adult neurogenesis is essential for the development of effective strategies to enhance endogenous neurogenesis in the damaged brain. Olfactory interneurons arise throughout life from stem cells residing in the subventricular zone of the lateral ventricle. Neural precursors then migrate along the rostral migratory stream (RMS) to the olfactory bulb. To ensure a continuous supply of adult-born interneurons, precursor proliferation, migration, and differentiation must be tightly coordinated. Here, we show that the netrin/repulsive guidance molecule receptor, Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neo(gt/gt)) mice exhibit a specific reduction in adult-born calretinin interneurons in the olfactory granule cell layer. In the absence of Neogenin, neuroblasts fail to migrate into the olfactory bulb and instead accumulate in the RMS. In vitro migration assays confirmed that Neogenin is required for Netrin-1-mediated neuroblast migration and chemoattraction. Unexpectedly, we also identified a novel role for Neogenin as a regulator of the neuroblast cell cycle. We observed that those neuroblasts able to reach the Neo(gt/gt) olfactory bulb failed to undergo terminal differentiation. Cell cycle analysis revealed an increase in the number of S-phase neuroblasts within the Neo(gt/gt) RMS and a significant reduction in the number of neuroblasts exiting the cell cycle, providing an explanation for the loss of mature calretinin interneurons in the granule cell layer. Therefore, Neogenin acts to synchronize neuroblast migration and terminal differentiation through the regulation of neuroblast cell cycle kinetics within the neurogenic microenvironment of the RMS.

Detecting degeneration: monitoring cognitive health in independent elders.

Australia has an ever increasing ageing population due to advances in healthcare and post-war booms in fertility. Estimations that over 22% of the population will be aged 65+ in 2050 provide a strong incentive to develop innovative assistive technologies to support elderly people to live safely at home longer. Extended independent living can improve quality of life for elders and their families and reduce costs associated with health and aged care. There is however, the need to monitor the elderly resident's safety, physical health and brain function. The Smarter Safer Homes project aims to develop a platform to facilitate independent living. The platform will aggregate sensor information at environmental, cognitive, physical, and physiological levels, allowing changes and trends in activities of daily living to be monitored. Such monitoring could potentially predict decline of brain function. Here we present how data derived from a sensor-based in-home monitoring system may be able to be used to provide a measure of neurological health. This measure could then facilitate tailoring of the home to meet the resident's changing needs, or to determine when a move to residential care is required.

Netrin-1: diversity in development.

In 1990, the discovery of three Caenorhabditis elegans genes (unc5, unc6, unc40) involved in pioneer axon guidance and cell migration marked a significant advancement in neuroscience research [Hedgecock EM, Culotti JG, Hall DH. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 1990;4:61-85]. The importance of this molecular guidance system was exemplified in 1994, when the vertebrate orthologue of Unc6, Netrin-1, was discovered to be a key guidance cue for commissural axons projecting toward the ventral midline in the rodent embryonic spinal cord [Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessell TM, Tessier-Lavigne M. The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 1994;78:409-424]. Since then, Netrin-1 has been found to be a critical component of embryonic development with functions in axon guidance, cell migration, morphogenesis and angiogenesis. Netrin-1 also plays a role in the adult brain, suggesting that manipulating netrin signals may have novel therapeutic applications.

Neogenin and RGMa control neural tube closure and neuroepithelial morphology by regulating cell polarity.

In humans, neural tube closure defects occur in 1:1000 pregnancies. The design of new strategies for the prevention of such common defects would benefit from an improved understanding of the molecular events underlying neurulation. Neural fold elevation is a key morphological process that acts during neurulation to drive neural tube closure. However, to date, the molecular pathways underpinning neural fold elevation have not been elucidated. Here, we use morpholino knock-down technology to demonstrate that Repulsive Guidance Molecule (RGMa)-Neogenin interactions are essential for effective neural fold elevation during Xenopus neurulation and that loss of these molecules results in disrupted neural tube closure. We demonstrate that Neogenin and RGMa are required for establishing the morphology of deep layer cells in the neural plate throughout neurulation. We also show that loss of Neogenin severely disrupts the microtubule network within the deep layer cells suggesting that Neogenin-dependent microtubule organization within the deep cells is essential for radial intercalation with the overlying superficial cell layer, thereby driving neural fold elevation. In addition, we show that sustained Neogenin activity is also necessary for the establishment of the apicobasally polarized pseudostratified neuroepithelium of the neural tube. Therefore, our study identifies a novel signaling pathway essential for radial intercalation and epithelialization during neural fold elevation and neural tube morphogenesis.

Neogenin is expressed on neurogenic and gliogenic progenitors in the embryonic and adult central nervous system.

The Netrin/RGMa receptor, Neogenin, has recently been identified on neuronal and gliogenic progenitors, including radial glia in the embryonic mouse cortex and ganglionic eminences, respectively [Fitzgerald, D.P., Cole, S.J., Hammond, A., Seaman, C., Cooper, H.M., 2006a. Characterization of Neogenin-expressing neural progenitor populations and migrating neuroblasts in the embryonic mouse forebrain. Neuroscience 142, 703-716]. Here we have undertaken a detailed analysis of Neogenin expression in the embryonic mouse central nervous system at key developmental time points. We demonstrate that Neogenin protein is present on actively dividing neurogenic precursors during peak phases of neurogenesis (embryonic days 12.5-14.5) in the forebrain, midbrain and hindbrain. Furthermore, we show that Neogenin protein is localized to the cell bodies and glial processes of neurogenic radial glial populations in all these regions. We have also observed Neogenin on gliogenic precursors within the subventricular zones of the forebrain late in development (embryonic day 17.5). Adult neural stem cells found in the subventricular zone of the lateral ventricle of the rodent forebrain are direct descendants of the embryonic striatal radial glial population. Here we show that Neogenin expression is maintained in the neural stem cell population of the adult mouse forebrain. In summary, this study demonstrates that Neogenin expression is a hallmark of many neural precursor populations (neurogenic and gliogenic) in both the embryonic and adult mammalian central nervous system.