Why neural stem cells may be vulnerable to Zika infection

This image shows a section through a stem cell-derived cerebral organoid (mini-brain in a dish) where the radial glia stem cells are shown in red, neurons are in blue, and the AXL receptors are in green. (Elizabeth Di Lullo)

Zika's hypothesized attraction to human neural stem cells may come from its ability to hijack a protein found on the surface of these cells, using it as an entryway to infection. In Cell Stem Cellon March 30, researchers at the University of California, San Francisco show that the AXL surface receptor, normally involved in cell division, is highly abundant on the surface of neural stem cells, but not on neurons in the developing brain.

The neural stem cells that express AXL are only present during the second trimester of pregnancy. These cells, called radial glial cells, give rise to the variety of cell types (e.g., neurons and astrocytes) that help build the cerebral cortex. The researchers also found AXL expressed by the stem cells of the retina. Disruption of this range of cell types is consistent with the multiple symptoms associated with Zika infection in the developing fetus--including microcephaly, a brain lacking in folds, and eye lesions.

"While by no means a full explanation, we believe that the expression of AXL by these cell types is an important clue for how the Zika virus is able to produce such devastating cases of microcephaly, and it fits very nicely with the evidence that's available," says senior study author Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. "AXL isn't the only receptor that's been linked with Zika infection, so next we need to move from 'guilt by association' and demonstrate that blocking this specific receptor can prevent infection."

Kriegstein's lab has a long-time interest in brain development. When the Zika outbreak hit, first authors Tomasz Nowakowski and Alex Pollen realized from previous studies that viruses similar to Zika--such as Dengue virus--seem to use AXL as an entry point to infection. They then used gene expression analysis (single-cell RNA sequencing) to look for AXL's presence across different cell types in mouse brain, ferret brain, human stem cell-derived brain organoids, and developing brain tissue in humans. Each of the models showed expression of AXL by the radial glial cells.

The researchers then used antibody trackers (immunohistochemistry) in the developing tissues and organoids to find out where the AXL receptor was most likely to be found on the neural stem cells. They found that AXL aggregates toward areas where the neural progenitors come into contact with either cerebrospinal fluid or blood vessels. This unique position would give a virus such as Zika an easy way to reach a vulnerable population of host cells.

"We still don't understand why Zika in particular is so virulent to the developing brain," Kriegstein says. "It could be that the virus travels more easily though the placental-fetal barrier or that the virus enters cells more readily than related infections."

Pending confirmation that Zika is using AXL for neural stem cell entry, the Kriegstein group is interested in exploring if the receptor could be exploited for therapeutic purposes. Since the protein is important for neural stem cell proliferation, it is unlikely that blocking AXL will be an option in the fetal brain. But perhaps there's a way to treat women at risk with an AXL inhibitor to stop Zika getting into the developing fetus in the first place.

This research was supported by the National Institutes of Health and the Damon Runyon Cancer Research Foundation.

Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.

Journal Reference:

Nowakowski et al. Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor. Cell Stem Cell, 2016 DOI: 10.1016/j.stem.2016.03.012

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Hydra can modify its genetic program

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This image shows the nervous system of about 1 cm-long Hydra revealed here with a fluorescent green marker.

Credit: © Brigitte Galliot

Date:

November 23, 2015

Source:

Université de Genève

Summary:

Champion of regeneration, Hydra is capable of reforming a complete individual from any fragment of its body. It is even able to remain alive when all its neurons have disappeared. Researchers have discovered how: cells of the epithelial type modify their genetic program by overexpressing a series of genes, among which some are involved in diverse nervous functions.

Champion of regeneration, the freshwater polyp Hydra is capable of reforming a complete individual from any fragment of its body. It is even able to remain alive when all its neurons have disappeared. Researcher the University of Geneva (UNIGE), Switzerland, have discovered how: cells of the epithelial type modify their genetic program by overexpressing a series of genes, among which some are involved in diverse nervous functions. Studying Hydra cellular plasticity may thus influence research in the context of neurodegenerative diseases. The results are published in Philosophical Transactions of the Royal Society.

The freshwater Hydra is endowed with an extraordinary power of regeneration, discovered by the Swiss naturalist Abraham Trembley more than 250 years ago. The group of Brigitte Galliot, professor at the Department of Genetics and Evolution of the Faculty of Science of UNIGE, has studied the stem cells functioning and cellular plasticity of the polyp: "its nervous system regulates in particular contraction bursts, feeding behavior, moving or swimming. If the stem cells responsible for its renewal are depleted, the Hydra can still develop, even when all its neurons have disappeared. We wanted to understand how this is possible."

Enhancing other cells' sensing ability

The researchers compared gene expression at various positions along the body axis in polyps devoid or not of their nervous stem cells. They observed a modification of the genetic program in animals depleted of these cells: "we identified 25 overexpressed genes in epithelial cells, the cells forming the Hydra's coating tissues. Some of these genes are involved in diverse nervous functions, such as neurogenesis or neurotransmission," says Yvan Wenger, co-first author of the article.

"Epithelial cells do not possess typical neuronal functions. However, Hydra's loss of neurogenesis induces epithelial cells to modify their genetic program accordingly, indicating that they are ready to assume some of these functions. These "naturally" genetically modified epithelial cells are thus likely to enhance their sensitivity and response to environmental signals, to partially compensate for the lack of nervous system," explains Wanda Buzgariu, co-first author of the article. The detail of these new functions remains to be discovered, as well as how epithelial cells proceed to overexpress these genes and thus adapt their genetic program.

Cellular plasticity maintains youth

Studying Hydra's cellular plasticity may be relevant in the context of neurodegenerative diseases. Indeed, some of the genes identified in this animal play an important role in cellular reprogramming or in neurogenesis in mammals. The researchers therefore wonder: would it be possible to restore sensing or secretion functions from other cell types, when some neurons degenerate?

This study also allows to go back to the origins of nervous systems. Epithelial cells most probably preceded nerve cells, performing some of their functions, although in a much slower way. "The loss of neurogenesis in Hydra may provide an opportunity to observe a reverse evolutive process, because it sheds light on a repressed ancestral genetic toolkit. An atavism of epithelial cells, when they most probably also possessed proto-neuronal functions," concludes Brigitte Galliot.

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Story Source:

The above post is reprinted from materials provided by Université de Genève. Note: Materials may be edited for content and length.

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Journal Reference:

1. Y. Wenger, W. Buzgariu, B. Galliot. Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells. Philosophical Transactions of the Royal Society, November 2015 DOI:10.1098/rstb.2015.0040

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Link made between genetics, aging

Rob Pazdro, left, and Yang Zhou led a study looking at a new pathway by which genetics regulates aging and disease. (Cal Powell/University of Georgia)

Scientists at the University of Georgia have shown that a hormone instrumental in the aging process is under genetic control, introducing a new pathway by which genetics regulates aging and disease.

Previous studies have found that blood levels of this hormone, growth differentiation factor 11, decrease over time. Restoration of GDF11 reverses cardiovascular aging in old mice and leads to muscle and brain rejuvenation, a discovery that was listed as one of the top 10 breakthroughs in science in 2014.

Scientists in the UGA College of Family and Consumer Sciences have now discovered that levels of this hormone are determined by genetics, representing another potential mechanism by which aging is encoded in the genome.

Future studies will seek to reveal why GDF11 levels decrease later in life and whether they can be sustained to prevent disease.

"Finding that GDF11 levels are under genetic control is of significant interest. Since it is under genetic control, we can find the genes responsible for GDF11 levels and its changes with age," said the study's senior author Rob Pazdro, an assistant professor in the college's department of foods and nutrition.

The study confirmed results from previous experiments showing that GDF11 levels decrease over time and also showed that most of the depletion occurs by middle age.

In addition, the study examined the relationship between GDF11 levels and markers of aging such as lifespan in 22 genetically diverse inbred mice strains. Of note, the strains with the highest GDF11 levels tended to live the longest.

Using gene mapping, Pazdro's team then identified seven candidate genes that may determine blood GDF11 concentrations at middle age, demonstrating for the first time that GDF11 levels are highly heritable.

"Essentially, we found a missing piece of the aging/genetics puzzle," Pazdro said. "Very generally, we've made an important step toward learning about aging and why we age and what are the pathways that drive it. It's the first step down a long road, but it's an important step."

The study, "Circulating Concentrations of Growth Differentiation Factor 11 are heritable and correlate with life span," was published in the Jan. 16 issue of the Journals of Gerontology Series A Biological Sciences and Medical Sciences.

Story Source:

The above story is based on materials provided by University of Georgia. Note: Materials may be edited for content and length.

Journal Reference:

Yang Zhou, Zixuan Jiang, Elizabeth C. Harris, Jaxk Reeves, Xianyan Chen, Robert Pazdro. Circulating Concentrations of Growth Differentiation Factor 11 Are Heritable and Correlate With Life Span. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2016; glv308 DOI: 10.1093/gerona/glv308

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AREAS OF RESEARCH in Biotechnology and Biochemistry

AREAS OF RESEARCH

* Aquaculture

* Biotechnology

* Bioinformatics

* Biological (renewable) energy

* Mineral Nutrition

* Metabolomics

* Photosynthesis

* Plant-Microbe Interactions

* Plant Molecular Biology

* Proteomics

* Signal Transduction

* Stress Phsyiology

* Value added/ material processing

* Biological production systems

* Bioremediation

* Environmental Biochemistry

* Functional Genomics

* Gene Regulation

* Genetics

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Regulate gene editing in wild animals

Gene editing is a hot topic following a flurry of interest in the use of CRISPR tools to modify human embryos. As an ethicist in a genome-engineering lab, I am an eyewitness to these recent scientific developments and I do have concerns about the way gene editing could be used. But they are not the concerns you might expect.

The ethical issues raised by human germline engineering are not new. They deserve consideration, but outcry over designer babies and precision gene therapy should not blind us to a much more pressing problem: the increasing use of CRISPR to edit the genomes of wild animal populations. Unless properly regulated and contained, this research has the potential to rapidly alter ecosystems in irreversible and damaging ways.

Scientists have already used CRISPR to modify mosquitoes and the fruit fly Drosophila melanogaster. And in combination with another molecular-biology technique called gene drive, they have found a way to massively increase the efficiency of spreading these transformations to offspring and through the population. Once introduced, these genetic changes are self-propagating. If released beyond the laboratory, the effects would spread with every new generation and would quickly run out of control.

Gene drive achieves rapid changes in a sexually reproducing population because it relies on genes that are capable of preferential spread through generations. Without this, introduced traits meet the statistical obstacle of Mendelian inheritance and take hold in a population much more slowly. Altering wild animal populations using gene drive aims to rapidly disrupt a particular trait, such as the ability of Anopheles mosquitoes to transmit malaria. It makes only a small-scale initial change to the relevant ecosystem and, in this example, the preliminary disruption would be restricted to the mosquito’s natural habitat. But the risk of broader ecosystem disruption is unknown and would require extensive mathematical modelling to estimate.

The gene-drive technique was developed in our lab, and in the initial publication of the method, my colleagues called for strict and validated biosafety measures and public review and consent (K. M. Esvelt et al. eLife 3, e03401; 2015). Meanwhile, work that combines CRISPR and gene-drive techniques is marching on. In what they call a “mutagenic chain reaction”, scientists at the University of California, San Diego, have used the combined approach to alter D. melanogaster(V. M. Gantz and E. Bier Science 348, 442–444; 2015). To me and others, this research raises serious and significant fears about biosafety. The work was done in a lab, but should any of the modified insects escape, they would be able to spread widely — unlike mosquitoes, which rely on ecological niches — and breed with the wild population. Experiments such as these should certainly be allowed, but only under the strictest conditions and with appropriate safeguards.

In less than three years, CRISPR has become a key tool for biologists. ‘Should they stop before it is too late?’ is therefore an immaterial question. Careful assessment of the various applications of CRISPR shows that there is no single or universal ethical evaluation that could cover all of them. The different consequences of human genome modification in either somatic cells or the germ line, and the modification of the ecosystem through gene drives, call for different ethical and policy evaluations.

Some critics argue that the unpredictable effects that human germline genome editing could have on future generations make it dangerous and ethically unacceptable. Uncertainty, however, is not a useful way to judge ethical acceptability. Others highlight the potential non-therapeutic purposes of germline modification. From the standpoint of ethics, it is not clear why trait modification is by definition a bad thing. Moreover, the criteria for what is therapy and what is ‘enhancement’ are fluid.

The consequences of modifying human genomes will be limited because effects will always be restricted to humans — the index person and their line of descendants. Biosafety and biosecurity risks are not apparent at this moment. Regulation, if and when it comes, might need to be adapted to the local situation, to existing legislation and to cultural and religious normative frameworks.

Presented in those terms, the human applications of CRISPR are much less troubling than the possibility of ecosystem modification. By definition, such disruption has more severe, complex, system-level consequences, and the breadth of its impact and the duration of its effects are hard to model. Gene drives are designed to be reversible, but this still needs to be tested. Self-propagating modified organisms cannot be contained within national borders and pose major challenges for regulation and governance. We therefore need an urgent review of biosafety and biosecurity protocols for experiments — both in the lab and in field-scale trials — that combine CRISPR and gene-drive techniques in wild organisms. Funders and institutions must lay out and enforce regulations.

The work with gene editing has thrown a useful spotlight on these bioengineering tools. But from an ethical perspective, the question we should ask is not what CRISPR can do for humans, but what humans can do with CRISPR.

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