A study suggests a disorder in prenatal neurogenesis in the development of ASD

A new study of autism risk genes by UC San Francisco and UC Berkeley scientists leads to a disorder in prenatal neurogenesis – a process in which specialized progenitor cells produce new brain cells – in development of autism spectrum disorders (ASDs). The study also shows that estrogen, possibly in a form extracted within brain cells, can protect against this disorder and direct the brain to a normal course of development.

The most interesting results of the study, published on January 25, 2021 in Neuron, extracted from experiments using embryos of the western claw frog (Xenopus tropicalis), a species that is appreciated by biologists for the unique perspectives it offers in terms of development. Human genes involved in development have similar functions to Xenopus, and extensive studies linking human embryonic levels to those of the frog mean that genetic studies in Xenopus may be directly relevant to human development in health and disease.

“Xenopus has been a cornerstone in developmental biology for many reasons, and much of what we know about human brain development is based on institutional research in frogs,” said Helen Rankin Willsey, PhD, postgraduate research in the laboratory of the Weill Institute for Neurosciences of co-author Matthew W. State, MD, PhD, Distinguished Oberndorf Family Professor and chair of the Department of Psychological and Behavioral Sciences at UCSF. “Frog brain development is very similar to human development, and many of the same genes, proteins and molecules that make up the human brain do the same thing in a developing frog brain. these factors make Xenopus an attractive species to win. a deeper understanding of neurodevelopmental problems. “

Over the past decade, genomic analyzes of humans, including many led by State and colleagues, have identified gene mutations that are strongly associated with ASD, allowing scientists together a collection of dozens of “high-confidence” genes that pose a high risk of developing them. disorders. With a growing knowledge of how, when, and where in the brain these genes influence development, autism researchers have begun to quantify in general terms what can be horrible. the RDDC.

Many of the identified mutations in genes are known to contribute to the formation and function of synapses – the communication sites between brain cells – and also to influence the correct orchestration at which genes are translated into proteins at the end. But the data behind these conclusions come from different and incomplete sources, and these known risk genes appear to be involved in different roles at different times during development. brain.

As a direct test of these ideas, and to find out if other developmental processes affected by these mutations were neglected, Willsey, the first author of the new study, turned to Xenopus, and brought together a laboratory. of the State with renowned developmental biologist Richard. Harland, PhD, Distinguished Professor of Genetics, Genomics and Development at UC Berkeley, and Jeremy Willsey, PhD at UCSF, assistant professor at the Institute for Neurodegenerative Diseases and Department of Psychological and Behavioral Sciences, leader in systems approaches -biology. to neurodevelopmental disorders,

Helen Willsey and her research team selected the “highest” ASD risk genes identified in humans to date, and then performed experiments assessing where and when their frogs are inserted. the brain the frog during development. They found that all ten were exposed to frog at a rate commensurate with human medieval development, which was well matched by computerized analyzes of autism-linked genes. made in 2013 by State and Jeremy Willsey, co-lead author of the paper update.

Xenopus females can lay more than 4,000 eggs at a time, which quickly develop into two-celled embryos large enough to be seen with the naked eye. Using high-throughput CRISPR gene targeting technology, Helen Willsey’s team eliminated each of the ten genes respectively, but in only one cell in the two-cell embryos – with this method, no inter- any developmental differences caused by the genetic change in just one half of the brain, and the other developing normally.

The ability to compare the two halves of the brain made it clear that there were large differences in size in the side of the brain in which the genes were disabled – when some genes were turned on half of the the impact was greater, with others it was smaller. But cellular and molecular functioning revealed that all of these size differences were due to the seeding of the neurogenesis process, which was manifested in atypical ratios of progenitor cells, precursors of brain cells, to mature neurons in the areas that line the ventricles of the forebrain.

Because researchers are as interested in resilience – ways to overcome the effects of the ASD gene – as they were at risk, they tested more than 130 drug compounds in the Xenopus embryos. One, associated with estrogen, restored a normal pattern of neurogenesis, with the resulting brain size on both sides of the animal.

On the other hand, when two other combinations that block the estrogen pathway were tested, neurogenesis was more disturbed. Xenopus gonads are not yet at the developmental stage at which the research team tested estrogen, so Willsey believes that estrogen may be secreted locally in the brain, rather than in sex organs. , provide protection from disturbances in neurogenesis during development.

Estrogen-related protective effects have also been observed in human neural progenitor cell lines in which several ASD risk genes have been blocked by a specific CRISPR mechanism, and also in similarly modified human brain organoids, 3D aggregates of cells that scientists use to study organ tension and development.

Willsey said that the ability of estrogen to reverse differential effects on neurogenesis and brain size resulting from the independent action of many different genes should be reassuring in an area where the rapid speed of gene detection is a concern. show that ASD may be too complex to treat. with medication.

Nevertheless, estrogen has profound effects on sex difference during development, and Willsey’s team showed that it regulates neurogenesis through a key signaling pathway called the Sonic hedgehog, which plays an important role in its development. everything from brain development to organ formation. The team’s estrogen identification should not be thought of as a protective factor, she said, but as a scientific toehold on the problem that may ultimately lead to the development of safer and more targeted treatments.

So many ASD genes have already been proven that it is possible to think that coming up with treatments that will be effective across a wide range of individuals is a difficult problem. But this work supports the idea that we can get a grip on this. These genes do different things, turn different gears, but our findings ultimately identify a critical nexus of ASD pathology and reveal a previously hidden biological connection binding a group of different genes. “

Helen Rankin Willsey, PhD, Postdoctoral Researcher