Source of Huntington's disease

Huntington's disease is a fatal hereditary disorder for which there is currently no treatment, it is associated with jerky movements and as these patients increasingly lose brain neurons, they slide into dementia. But the new research suggests that these symptoms may be a late manifestation of a disease that originates much earlier, in the first steps of embryonic development.

A team at Rockefeller led by Ali Brivanlou, the Robert and Harriet Heilbrunn Professor, developed a system to model Huntington's in human embryonic stem cells for the first time. Researchers describe early abnormalities in the way Huntington's neurons look, and how these cells form larger structures that had not previously been associated with the disease.

Huntington's is one of the few diseases with a straightforward genetic culprit: One hundred percent of people with a mutated form of the Huntingtin (HTT) gene develop the disease. The mutation takes the form of extra DNA, and causes the gene to produce a longer-than-normal protein. The DNA itself appears in the form of a repeating sequence, and the more repeats there are, the earlier the disease sets in.

Research on Huntington's has thus far relied heavily on animal models of the disease, and has left many key questions unanswered. For example, scientists have not been able to resolve what function the HTT gene serves normally, or how its mutation creates problems in the brain. Suspecting that the disease works differently in humans, whose brains are much bigger and more complex than those of lab animals, researchers developed a cell-based human system for their research. They used the gene editing technology CRISPR to engineer a series of human embryonic stem cell lines, which were identical apart from the number of DNA repeats that occurred at the ends of their HTT genes.

In cell lines with mutated HTT, we saw giant cells. It looked like a jungle of disorganization. When cells divide, they typically each retain one nuclei. However, some of these enlarged, mutated cells flaunted up to 12 nuclei-suggesting that neurogenesis, or the generation of new neurons, was affected. The disruption was directly proportional to how many repeats were present in the mutation: The more repeats there were, the more multinucleated neurons appeared.

There is an unrecognized developmental aspect to the pathology. Huntington's may not be just a neurodegenerative disease, but also a neurodevelopmental disease. Treatments for Huntington's have typically focused on blocking the activity of the mutant HTT protein, the assumption being that the altered form of the protein was more active than normal, and therefore toxic to neurons. However, Brivanlou's work shows that the brain disruption may actually be due to a lack of HTT protein activity.

To test its function, the researchers created cell lines that completely lacked the HTT protein. These cells turned out to be very similar to those with Huntington's pathology, corroborating the idea that a lack of the protein not an excess of it is driving the disease. The findings are significant because existing treatments that were designed to block HTT activity may actually do more harm than good.
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Roles of Mesp1 gene

Researchers at the Université libre de Bruxelles and University of Cambridge identified the role of key gene Mesp1 in the earliest step of cardiovascular lineage segregation. This discovery may help to better understand congenital heart defects. The heart is the first organ that forms during development and contains four regions (ventricles and atria), which contain cells that perform specialized functions: the beating cardiomyocytes ensure the pumping activity, vascular cells represent the inner lining and blood vessels, and the pacemaker cells regulate the heartbeat.

Unless the progenitor cells are specified at the correct time, migrate to the correct location, and differentiate into the correct cell types, severe malformations of the heart occur. In human patients, these are recognized as congenital heart diseases, which represent the most common cause of severe birth defects in newborn babies. Previous studies had shown that a diverse range of heart progenitor cells arises from different pools of cells expressing the Mesp1 gene. However, it remained unclear how the various progenitors can be distinguished at the molecular level, and what molecular mechanisms promote specification into a particular heart region or cardiac lineage.

Researchers led by Pr. Cédric Blanpain, Laboratory of Stem Cells and Cancer, Université libre de Bruxelles, Belgium, and Pr. Berthold Göttgens, the University of Cambridge, identified the role of Mesp1 in the earliest step of cardiovascular lineage segregation by single cell molecular profiling and lineage tracking. Fabienne Lescroart and colleagues isolated Mesp1 expressing cells at different stages of embryonic development and performed single cell transcriptomic analysis of these early cardiac progenitors to identify the molecular features associated with regional and cell type identity of cardiac progenitors.

They demonstrated that the different populations of cardiac progenitors are molecularly distinct. To determine the role of the transcription factor Mesp1 in regulating the cardiovascular differentiation program and the heterogeneity of early cardiovascular progenitors, they also performed single cell molecular profiling of these early progenitors in a Mesp1 deficient context. These experiments showed that Mesp1 is required for the exit from the pluripotent state and the induction of the cardiovascular gene expression program.

Bioinformatic analysis identified, among these early Mesp1 progenitors, distinct populations of cells corresponding to progenitors committed to different cell lineages and regions of the heart, identifying the molecular features associated with early lineage restriction and regional segregation of the heart. While progenitor cells are not yet differentiated, this new analysis shows that cardiovascular progenitors are already "primed" or pre-specified to give rise to cardiac muscle cells or vascular cells. The researchers found that these different populations are also born at different time points and are located at specific locations at this early stage of development.

The researchers have identified the earliest branching point between the cardiac and vascular lineages, and shown that Notch1 marks the early progenitor committed to the vascular lineage during early embryonic development. Understanding the molecular features associated with early cardiovascular lineage commitment and heart regions will be important to design new strategies to instruct cardiovascular progenitors to adopt cardiac or vascular identity from different heart regions that can be used for cellular therapy of cardiac diseases.
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MicroRNA regulates movements of tumour cells

Cancer cells can reactivate a cellular process that is an essential part of embryonic development. This allows them to leave the primary tumor, penetrate the surrounding tissue and form metastases in peripheral organs.

During an embryo's development, epithelial cells can break away from the cell cluster, modify their cell type-specific properties, and migrate into other regions to form the desired structures. This process is known as an epithelial–mesenchymal transition EMT is reversible and can also proceed in the direction from mesenchymal cells to epithelial cells (MET).

It is repeated multiple times during embryonic development and ultimately paves the way for the formation of organs in the human body. Tumor cells can reactivate the program. Although this is a completely normal process during embryogenesis, it also plays an important role in the spread of tumor cells within the body and in the formation of metastases.

Tumor cells are able to reactivate the EMT/MET program. By doing so, they obtain characteristics of stem cells and develop strong resistance to classical and state-of-the-art targeted cancer therapies. An EMT also makes it easier for cancer cells to break away from the primary tumor, to penetrate into surrounding tissue and into blood vessels, to spread throughout the body and to form metastases in distant organs, which is ultimately responsible for the death of most cancer patients.

Regulation the cellular EMT program prevents the development of malignant tumors and the formation of metastases such as in the case of breast cancer, researchers focused specifically on microRNAs (miRNAs), a class of very short non-coding RNAs with a considerable effect on gene regulation.
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How Zika virus infects developing brain

Zika virus is transmitted from mother to fetus by infected cells that later develop into the brain's first and primary form of defense against invasive pathogens. During embryogenesis- the early stages of prenatal development cells called microglia form in the yolk sac and then disperse throughout the central nervous system CNS of the developing fetus.

In the brain, these microglia will become resident macrophages whose job is to constantly clear away plaques, damaged cells and infectious agents. The Zika virus can infect these early microglia, moving into the brain where they transmit the virus to other brain cells, leading to devastating neurological damage.

The Zika virus is transmitted to people through the bite of infected Aedes species mosquitoes. However, a pregnant woman can also pass the virus to her fetus, the researchers used human induced pluripotent stem cells to create two relevant CNS cell types: microglia and neural progenitor cells (NPCs), which generate the millions of neurons and glial cells required during embryonic development.

Then they established a co-culture system that mimicked the interactions of the two cell types in vitro when exposed to the Zika virus. They discovered that the microglia cells engulfed Zika-infected NPCs, doing their job. But when these microglia carrying the virus were placed in contact with non-infected NPCs, they transmitted the virus to the latter.
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RNA modification and brain development

A chemical tag added to RNA during embryonic development regulates how the early brain grows, when this development goes wrong, it may cause psychiatric disorders in people. Researchers used animal models and mini-brains, made from human stem cells to relate their findings to conditions found in people.

Researchers have discovered chemical modifications to messenger RNA mRNA across the genome at certain sites and found that these changes are dynamic- a specific chemical group is added and taken off by enzymes in a regular, pattern. The chemical group studied in the Cell paper, m6A, is the most prevalent modification to mRNA in human cells.

The current thinking is that a tightly controlled molecular process guides the complicated development of the brain before birth and the process relies on a precise sequence of genes being turned on and off. However, even subtle mistakes in this process can become serious issue. The classic view of this control is that DNA codes for RNA, guiding which proteins will be made by cells. However, mRNA can be modified along the way so that it can produce proteins with many variations.

A new field called epitranscriptomics was discovered during the research. The Cell paper is the first study of epitranscriptomics in the embryonic mammalian brain, and the key is m6A, a marker for molecules bound for disposal within the cell. Normally, m6A-tagged mRNAs are related to such processes as cell replication and neuron differentiation, and m6A-tagging promotes their decay after they are no longer needed.

If m6A is not added on the correct time schedule to a garbage-bound molecule, the developmental train goes down the wrong tracks because developing brain cells get stuck at an earlier stage because the m6A cues for taking out the cellular trash are misread or not read at all. The researchers found that in a mouse model with depleted m6A, cell replication is prolonged, so that stem-cell differentiation, which normally reels out daughter cells in an orderly fashion, gets stuck. The knockout mouse develops less brain cells such as neurons and glia cells, and therefore has abnormal circuitry and a non-functioning brain.

Neuron development in the mini-brains that was developed is similar to what happens in people, modeling fetal brain development up to the second trimester. Human stem cells had a greater number of m6A tags compared to mouse cells. Many of the genes associated with genetic risk for certain conditions, such as schizophrenia and autism spectrum disorder, are only m6A-tagged in humans, not in mice, raising the possibility that dysregulation at this level of gene expression may contribute to certain human brain disorders.
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