neural progenitor cells

Scientists Uncover Common Cell Signaling Pathway Awry in Some Types of Autism

Brain cells grow faster in children with some forms of autism due to distinct changes in core cell signaling patterns, according to research from the laboratory of Anthony Wynshaw-Boris, MD, PhD, chair of the department of genetics and genome sciences at Case Western Reserve University School of Medicine, and a member of the Case Comprehensive Cancer Center. Rapid cell growth can cause early brain overgrowth, a common feature in 20-30% of autistic children. But, the genetics of autistic children vary making it difficult to pinpoint common mechanisms underlying the disease.

“Autism is a complex disorder with multiple genetic and non-genetic factors,” explained Wynshaw-Boris. “Because the causes are diverse, it may help to define a subset of patients that have a common [symptom], in this case early brain overgrowth.”

In a study published in Molecular Psychiatry, Wynshaw-Boris and his colleagues started with skin cell samples from autistic children with enlarged brains and worked backward. Researchers in the laboratory “reprogrammed” donated skin cells to produce cells found in the developing brain including induced pluripotent stem cells and neural progenitor cells. Stem and progenitor cells are important therapeutic tools as they have the potential to grow into a multitude of cell types. The researchers hypothesized that even though the children in the study had different forms of autism, the precursor cells could be used to find common molecular and cellular mechanisms.

The researchers discovered that cells derived from autistic donors grew faster than those from control subjects and activated their genes in distinct patterns. Genes related to cell growth were unusually active, leading to more cells but fewer connections between them. This can cause faulty cell networks unable to properly transmit signals in the brain and enlarged heads during early development.

The researchers identified abnormal genes in the cells grown from autistic donors as belonging to the Wnt signaling pathway. The Wnt genes are critical for cell growth and serve as central players in cell networks, interfacing with multiple signaling pathways. Wynshaw-Boris previously identified the Wnt pathway as related to autism in mouse models of the disease. In a separate study published in Molecular Psychiatry earlier this year, the Wynshaw-Boris laboratory showed mice lacking Wnt genes display autism-like symptoms including social anxiety and repetitive behavior. The researchers could prevent these adult symptoms by treating the mice with medications that activate Wnt signaling in the uterus, during development.

“The Wnt pathway is one of the core developmental pathways conserved from invertebrates to humans. Our studies solidify previous suggestions that this pathway has a role in autism,” said Wynshaw-Boris.

Once they identified the dysfunctional signaling pathway in their reprogrammed autistic samples, the researchers (including the laboratories of Alysson Muotri, PhD at the University of California San Diego and Fred Gage, PhD at the Salk Institute) attempted to correct it by exposing mature nerve cells derived from autistic donors to drug compounds. One drug currently being tested in clinical trials for autism is insulin growth factor 1 (IGF-1). When the researchers added IGF-1 to nerve cells derived from autistic donors, neural networks were reestablished. It is unclear whether the positive effects of IGF-1 were on the Wnt pathway, and the exact compensatory mechanism requires further investigation.

Wynshaw-Boris’s studies in cell culture and mouse models of autism confirm improper Wnt signaling can lead to rapid brain cell growth and brain enlargement in the embryo, resulting in abnormal social behavior after birth. The next step will be to determine which genes are most impacted by Wnt signaling defects during early development, and how these changes result in abnormal behavior. “We would also like to find other drugs or compounds that may slow down the growth of the cells in tissue culture,” said Wynshaw-Boris. Together, these findings may help researchers unravel common ways brain cells can become impaired during early development in carefully chosen subsets of patients and contribute to symptoms across the autism spectrum.

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Zika can infect adult brain cells, not just fetal cells, study suggests
A study in mice suggests that Zika virus could damage brain areas responsible for learning and memory.

The more researchers learn about the Zika virus, the worse it seems.

A growing body of research has established that the virus can cause severe birth defects — most notably microcephaly, a condition characterized by an abnormally small head and often incomplete brain development. The virus also has been linked to cases of Guillain-Barre syndrome in adults, a rare autoimmune disorder that can result in paralysis and even death.

Now, in a study in mice, researchers have found evidence that suggests adult brain cells critical to learning and memory also might be susceptible to the Zika virus.

“This was kind of a surprise,” Joseph Gleeson, a professor at Rockefeller University and one of the co-authors of the study published Thursday in the journal Cell Stem Cell, said in an interview. “We think of Zika health concerns being limited mostly to pregnant women.”

[For Zika-infected pregnancies, microcephaly risk may be as high as 13 percent]

In a developing fetus, the brain is made primarily of “neural progenitor” cells, a type of stem cell. Researchers believe these cells are especially susceptible to infection by the Zika virus, which can hinder their development and disrupt brain growth. Most adult neurons are believed to be resistant to Zika, which could explain why adults seem less at risk from the virus’s most devastating effects.

But some neural progenitor cells remain in adults, where they replenish the brain’s neurons over the course of a lifetime. These pockets of stem cells are vital for learning and memory. Gleeson and his colleagues suspected that if Zika can infect fetal neural progenitor cells, the virus might have the same ability to infect adult neural progenitor cells. That’s precisely what they found.

“We asked whether [these cells] were vulnerable to Zika in the same way the fetal brain is,” Glesson said. “The answer is definitely yes.”

Gleeson is the first to admit that the findings represent only an initial step in discovering whether Zika can endanger adult human brain cells. For starters, the study was conducted only in mice, and only at a single point in time. More research will be necessary to see whether the results of the mouse model translates to humans, and whether the damage to adult brain cells can cause long-term neurological damage or affect behavior.

But the initial findings suggest that the Zika virus, which has spread to the United States and more than 60 other countries over the past year, may not be as innocuous as it seems for adults, most of whom never realize they have been infected. Researchers found that infected mice had more cell death in their brains and reduced generation of new neurons, which is key to learning and memory. The possible consequences of damaged neural progenitor cells in humans would include cognitive problems and a higher likelihood for conditions such as depression and Alzheimer’s disease.

[Obama administration to shift $81 million to fight Zika]

“Zika can clearly enter the brain of adults and can wreak havoc,” Sujan Shresta, another study co-author and a professor at the La Jolla Institute of Allergy and Immunology, said in a statement. “But it’s a complex disease — it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle, and now we know what to look for.”

William Schaffner, an infectious disease expert at Vanderbilt University Medical Center, agreed Thursday that the findings are preliminary. But he also called it troubling.

“Here’s the deal — the more we’ve learned about the Zika virus, the nastier it is,” said Schaffner, who was not involved in the study. He said scientists have had concerns all along about Zika’s ability to damage the brain, but until now the worries have focused mostly on the developing brain. “This mouse study will increase our anxiety. … It’s an additional potential way that this virus can cause human illness.”

That’s a possibility that demands further examination, he said, given the hundreds of thousands of people already infected by Zika — a number that continues to grow daily.

“Our attention, quite understandably, has been devoted to pregnant women and newborns, and preventing those infections,” Schaffner said. “This mouse study will tell investigators that, in addition to pregnant women, you have to establish some studies in older children and adults as well.”

Gleeson agreed. “We don’t want to have this be a panic. Zika, for the most part, is a benign condition in healthy humans,” he said. “But we also need to look at the potential consequences in a careful way.”

Researchers observe stem cell specialization in the brain

Adult stem cells are flexible and can transform themselves into a wide variety of special cell types. Because they are harvested from adult organisms, there are no ethical objections to their use, and they therefore open up major possibilities in biomedicine. For instance, adult stem cells enable the stabilization or even regeneration of damaged tissue. Neural stem cells form a reservoir for nerve cells. Researchers hope to use them to treat neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. Tübingen researchers led by Professor Olga Garaschuk of the University of Tübingen’s Institute for Physiology, working with colleagues from Yale University, the Max Planck Institute of Neurobiology in Martinsried and the Helmholtz Center in Munich, studied the integration of these cells into the pre-existing neural network in the living organism. The results of their study have been published in the latest edition of Nature Communications.

There are only two places in the brains of adult mammals where stem cells can be found – the lateral ventricles and the hippocampus. These stem cells are generating neurons throughout life. The researchers focused on a stem cell zone in the lateral ventricle, from where progenitors of the nerve cells migrate towards the olfactory bulb. The olfactory nerves which start in the nasal tissue run down to this structure, which in mice is located at the frontal base of the brain. It is there that the former stem cells specialized in the task of processing information on smells detected by the nose. “Using the latest methods in microscopy, we were for the first time able to directly monitor functional properties of migrating neural progenitor cells inside the olfactory bulb in mice,” says Olga Garaschuk. The researchers were able to track the cells using special fluorescent markers whose intensity changes according to the cell’s activity.

The study showed that as little as 48 hours after the cells had arrived in the olfactory bulb, around half of them were capable of responding to olfactory stimuli. Even though the neural progenitor cells were still migrating, their sensitivity to odorants and their electrical activity were similar to those of the surrounding, mature neurons. The mature pattern of odor-evoked responses of these cells strongly contrasted with their molecular phenotype which was typical of immature, migrating neuroblasts. “Our data reveal a remarkably rapid functional integration of adult-born cells into the pre-existing neural network,” says Garaschuk, “and they show that sensory-driven activity is in a position to orchestrate their migration and differentiation as well as their decision of when and where to integrate.”