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Zebrafish turn the tide in autism research
CAMBRIDGE, Mass.—Research biologists at the Massachusetts Institute of Technology (MIT) School of Science are counting on the small, luminous bluish-black and silvery-gold striped zebrafish to unlock the mystery of autism. While the popular aquarium fish cannot display symptoms of autism, schizophrenia or other human brain disorders, the organism is a useful tool for studying the genes that contribute to such disorders—and has the potential for new information on the genes that cause autism, according to a study led by Hazel Sive, associate dean and developmental biologist at MIT.
And while the zebrafish holds much promise for the future of treating, curing and possibly preventing autism from occurring, scientists are swimming against the current in search of simple answers.
"We chose the fish as it is a wonderful system to study genetic and molecular pathways that underlie gene function in the whole animal," Sive tells ddn. "Assays can be much more extensive than they can be in mice over the same timeframe. Since human and fish genes are similar, we can almost always find a fish gene that matches a human disease risk gene. And since there is so little known about autism risk genes and how they work, the zebrafish can be an entry point to new analyses of such genes."
Sive and her colleagues described their findings in an article published in the online edition of the journal Disease Models & Mechanisms (DMM). First, researchers isolated and studied a group of about two dozen genes known to be either missing or duplicated in about 1 percent of autistic patients. Most of the genes' functions were unknown, but the MIT study revealed that nearly all of them produced brain abnormalities when deleted in zebrafish embryos.
"Specifically, we wanted to know how many genes in this region were necessary for brain development, and which were 'dosage sensors' that gave phenotypes with small
increases or decreases in expression," Sive says. "We wanted to figure out which genes in this and other genomic intervals work together to confer copy number dependent phenotypes, and to use the fish to define potential diagnostics and therapies."
In the DMM journal summary, researchers explain that deletion or duplication of one copy of the human 16p11.2 interval is tightly associated with impaired brain function, including autism spectrum disorders, intellectual disability disorder and other phenotypes, indicating the importance of gene dosage in this copy number variant (CNV) region.
Using the zebrafish as a tool, a set of 16p11.2 homologs was identified, primarily on chromosomes 3 and 12, the study states. Use of 11 phenotypic assays, spanning the first five days of development, demonstrated that this set of genes is highly active in that 21 out of the 22 homologs tested showed loss-of-function phenotypes.
Most genes in this region were required for nervous system development—impacting brain morphology, eye development, axonal density or organization and motor response, the research found. In general, human genes were able to substitute for the fish homolog, demonstrating orthology and suggesting conserved molecular pathways.
Furthermore, the researchers were able to restore normal development by treating the fish with the human equivalents of the genes that had been repressed, allowing researchers "to deduce that what you're learning in fish corresponds to what that gene is doing in humans," Sive says.
The genes in the 16p11.2 CNV are probably integral to normal brain function, the research article states. Of the 25 genes in the central core interval, it is hypothesized that dosage changes in one or more of these genes underlie the pathologies associated with the 16p11.2 CNV.
However, the article also states that the crucial genes in the 16p11.2 interval—and in many CNVs associated with other disorders—are unknown.
The future for this research includes further experiments to understand the molecular pathways by which each gene works, and whether each works together with other genes in the 16p11.2 interval, as predicted by human genetic data, the article concluded. This information will help to define targeted assays in mammals and possibly guide therapeutic directions.
Since autism is thought to arise from a variety of genetic defects, this research is part of a broad effort to identify culprit genes and develop treatments that target them, Sive says.
"That's really the goal—to go from an animal that shares molecular pathways, but doesn't get autistic behaviors, into humans who have the same pathways and do show these behaviors," says Sive, who is also a member of the Whitehead Institute for Biomedical Research.