Analysis of Expression Pattern and Genetic Deletion of Netrin5 in the Developing Mouse

Boundary cap cells are a transient, neural-crest-derived population found at the motor exit point and dorsal root entry zone of the embryonic spinal cord. These cells contribute to the central/peripheral nervous system boundary, and in their absence neurons and glia from the CNS migrate into the PNS. We found Netrin5 (Ntn5), a previously unstudied member of the netrin gene family, to be robustly expressed in boundary cap cells. We generated Ntn5 knockout mice and examined neurodevelopmental and boundary-cap-cell-related phenotypes. No abnormalities in cranial nerve guidance, dorsal root organization, or sensory projections were found. However, Ntn5 mutant embryos did have ectopic motor neurons that migrated out of the ventral horn and into the motor roots. Previous studies have implicated semaphorin6A (Sema6A) in boundary cap cells signaling to plexinA2 (PlxnA2)/neuropilin2 (Nrp2) in motor neurons in restricting motor neuron cell bodies to the ventral horn, particularly in the caudal spinal cord. In Ntn5 mutants, ectopic motor neurons are likely to be a different population, as more ectopias were found rostrally. Furthermore, ectopic motor neurons in Ntn5 mutants were not immunoreactive for NRP2. The netrin receptor DCC is a potential receptor for NTN5 in motor neurons, as similar ectopic neurons were found in Dcc mutant mice, but not in mice deficient for other netrin receptors. Thus, Ntn5 is a novel netrin family member that is expressed in boundary cap cells, functioning to prevent motor neuron migration out of the CNS

Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology.

Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD), and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical in mice for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant mouse embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, including mTOR activation, the translatome and mouse cerebellar development were observed upon deletion of the NMD factor Upf2. Our data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses

How does democracy influence citizens' perceptions of government corruption? A cross-national study

We examine the effect of democracy as an institutional context on individuals’ perceptions of government corruption. To do so, we compile an integrated dataset from the Asian, Afro, and Latino Barometer Surveys and use a hierarchical linear regression model. Our primary finding is that the effect of democracy has different effects on ordinary citizens’ perceptions of corruption in different contexts. In general, people in countries with higher levels of democracy tend to perceive their governments to be more corrupt. However, more importantly, conditional models show that in countries with more developed democratic institutions, individuals with stronger democratic values are less likely to perceive the government to be corrupt. Moreover, people in such countries are less likely to assess their government based on their perceptions of economic situation

Waterfowl recently infected with low pathogenic avian influenza exhibit reduced local movement and delayed migration

Understanding relationships between infection and wildlife movement patterns is important for predicting pathogen spread, especially for multispecies pathogens and those that can spread to humans and domestic animals, such as avian influenza viruses (AIVs). Although infection with low pathogenic AIVs is generally considered asymptomatic in wild birds, prior work has shown that influenza-infected birds occasionally delay migration and/or reduce local movements relative to their uninfected counterparts. However, most observational research to date has focused on a few species in northern Europe; given that influenza viruses are widespread globally and outbreaks of highly pathogenic strains are increasingly common, it is important to explore influenza–movement relationships across more species and regions. Here, we used telemetry data to investigate relationships between influenza infection and movement behavior in 165 individuals from four species of North American waterfowl that overwinter in California, USA. We studied both large-scale migratory and local overwintering movements and found that relationships between influenza infection and movement patterns varied among species. Northern pintails (Anas acuta) with antibodies to avian influenza, indicating prior infection, made migratory stopovers that averaged 12 days longer than those with no influenza antibodies. In contrast, greater white-fronted geese (Anser albifrons) with antibodies to avian influenza made migratory stopovers that averaged 15 days shorter than those with no antibodies. Canvasbacks (Aythya valisineria) that were actively infected with influenza upon capture in the winter delayed spring migration by an average of 28 days relative to birds that were uninfected at the time of capture. At the local scale, northern pintails and canvasbacks that were actively infected with influenza used areas that were 7.6 and 4.9 times smaller than those of uninfected ducks, respectively, during the period of presumed active influenza infection. We found no evidence for an influence of active influenza infection on local movements of mallards (Anas platyrhynchos). These results suggest that avian influenza can influence waterfowl movements and illustrate that the relationships between avian influenza infection and wild bird movements are context- and species-dependent. More generally, understanding and predicting the spread of multihost pathogens requires studying multiple taxa across space and time

Pathways for avian influenza virus spread: GPS reveals wild waterfowl in commercial livestock facilities and connectivity with the natural wetland landscape

Zoonotic diseases are of considerable concern to the human population and viruses such as avian influenza (AIV) threaten food security, wildlife conservation and human health. Wild waterfowl and the natural wetlands they use are known AIV reservoirs, with birds capable of virus transmission to domestic poultry populations. While infection risk models have linked migration routes and AIV outbreaks, there is a limited understanding of wild waterfowl presence on commercial livestock facilities, and movement patterns linked to natural wetlands. We documented 11 wild waterfowl (three Anatidae species) in or near eight commercial livestock facilities in Washington and California with GPS telemetry data. Wild ducks used dairy and beef cattle feed lots and facility retention ponds during both day and night suggesting use for roosting and foraging. Two individuals (single locations) were observed inside poultry facility boundaries while using nearby wetlands. Ducks demonstrated high site fidelity, returning to the same areas of habitats (at livestock facilities and nearby wetlands), across months or years, showed strong connectivity with surrounding wetlands, and arrived from wetlands up to 1251 km away in the week prior. Telemetry data provides substantial advantages over observational data, allowing assessment of individual movement behaviour and wetland connectivity that has significant implications for outbreak management. Telemetry improves our understanding of risk factors for waterfowl–livestock virus transmission and helps identify factors associated with coincident space use at the wild waterfowl–domestic livestock interface. Our research suggests that even relatively small or isolated natural and artificial water or food sources in/near facilities increases the likelihood of attracting waterfowl, which has important consequences for managers attempting to minimize or prevent AIV outbreaks. Use and interpretation of telemetry data, especially in near-real-time, could provide key information for reducing virus transmission risk between waterfowl and livestock, improving protective barriers between wild and domestic species, and abating outbreaks

Cell-cell adhesion proteins in melanocytic pilomatrix carcinoma

Tumors of the matrix of rigid structures include matrical tumors of the hairs, nails, and teeth. These tumors share similar phenotypical and signaling features. Although benign matrical hair tumors are among the most common of these tumors, hair matrix tumors containing pigmented melanocytes are very rare. The malignant variant called melanocytic pilomatrix carcinoma contains benign colonizing dendritic melanocytes admixed with the carcinomatous follicular matrical cells

Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco–Sjögren syndrome

Endoplasmic reticulum (ER) stress has been linked to the onset and progression of many diseases. SIL1 is an adenine nucleotide exchange factor of the essential ER lumen chaperone HSPA5/BiP that senses ER stress and is involved in protein folding. Mutations in the Sil1 gene have been associated with Marinesco–Sjögren syndrome, hallmarks of which include ataxia and cerebellar atrophy. We have previously shown that loss of SIL1 function in mouse results in ER stress, ubiquitylated protein inclusions, and degeneration of specific Purkinje cells in the cerebellum. Here, we report that overexpression of HYOU1/ORP150, an exchange factor that works in parallel to SIL1, prevents ER stress and rescues neurodegeneration in Sil1−/− mice, whereas decreasing expression of HYOU1 exacerbates these phenotypes. In addition, loss of DNAJC3/p58IPK, a co-chaperone that promotes ATP hydrolysis by BiP, ameliorates ER stress and neurodegeneration in Sil1−/− mice. These findings suggest that alterations in the nucleotide exchange cycle of BiP cause ER stress and neurodegeneration in Sil1-deficient mice. Our results present the first evidence of important genetic modifiers of Marinesco–Sjögren syndrome, and provide additional pathways for therapeutic intervention for this, and other ER stress-induced, diseases

A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation

Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln) and toppler (to), with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydro)ceramide synthase 1 (CerS1), which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases