Zebrafish turn the tide in autism research

MIT researchers turn to fish models to uncover secrets of autism

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CAMBRIDGE, Mass.—Research biologists at the MassachusettsInstitute of Technology (MIT) School of Science are counting on the small,luminous bluish-black and silvery-gold striped zebrafish to unlock the mysteryof autism. While the popular aquarium fish cannot display symptoms of autism,schizophrenia or other human brain disorders, the organism is a useful tool forstudying the genes that contribute to such disorders—and has the potential fornew information on the genes that cause autism, according to a study led byHazel Sive, associate dean and developmental biologist at MIT.
And while the zebrafish holds much promise for the future oftreating, curing and possibly preventing autism from occurring, scientists areswimming against the current in search of simple answers.
"We chose the fish as it is a wonderful system to studygenetic and molecular pathways that underlie gene function in the wholeanimal," Sive tells ddn. "Assays canbe much more extensive than they can be in mice over the same timeframe. Sincehuman and fish genes are similar, we can almost always find a fish gene thatmatches a human disease risk gene. And since there is so little known aboutautism risk genes and how they work, the zebrafish can be an entry point to newanalyses of such genes."
Sive and her colleagues described their findings in anarticle published in the online edition of the journal Disease Models & Mechanisms (DMM).First, researchers isolated and studied a group of about two dozen genesknown to be either missing or duplicated in about 1 percent of autisticpatients. Most of the genes' functions were unknown, but the MIT study revealedthat nearly all of them produced brain abnormalities when deleted in zebrafishembryos.
"Specifically, we wanted to know how many genes in thisregion were necessary for brain development, and which were 'dosage sensors'that gave phenotypes with small
increases or decreases in expression," Sive says. "We wantedto figure out which genes in this and other genomic intervals work together toconfer copy number dependent phenotypes, and to use the fish to definepotential diagnostics and therapies."
In the DMM journalsummary, researchers explain that deletion or duplication of one copy of thehuman 16p11.2 interval is tightly associated with impaired brain function,including autism spectrum disorders, intellectual disability disorder and otherphenotypes, indicating the importance of gene dosage in this copy numbervariant (CNV) region.
Using the zebrafish as a tool, a set of 16p11.2 homologs wasidentified, primarily on chromosomes 3 and 12, the study states. Use of 11phenotypic assays, spanning the first five days of development, demonstratedthat this set of genes is highly active in that 21 out of the 22 homologstested showed loss-of-function phenotypes.
Most genes in this region were required for nervous systemdevelopment—impacting brain morphology, eye development, axonal density ororganization and motor response, the research found. In general, human geneswere able to substitute for the fish homolog, demonstrating orthology andsuggesting conserved molecular pathways.
Furthermore, the researchers were able to restore normaldevelopment by treating the fish with the human equivalents of the genes thathad been repressed, allowing researchers "to deduce that what you're learningin fish corresponds to what that gene is doing in humans," Sive says.
The genes in the 16p11.2 CNV are probably integral to normalbrain function, the research article states. Of the 25 genes in the centralcore interval, it is hypothesized that dosage changes in one or more of thesegenes underlie the pathologies associated with the 16p11.2 CNV.
 However, the article also states that the crucial genes inthe 16p11.2 interval—and in many CNVs associated with other disorders—areunknown.
The future for this research includes further experiments tounderstand the molecular pathways by which each gene works, and whether eachworks together with other genes in the 16p11.2 interval, as predicted by humangenetic data, the article concluded. This information will help to definetargeted assays in mammals and possibly guide therapeutic directions.
Since autism is thought to arise from a variety of geneticdefects, this research is part of a broad effort to identify culprit genes anddevelop treatments that target them, Sive says.
"That's really the goal—to go from an animal that sharesmolecular pathways, but doesn't get autistic behaviors, into humans who havethe same pathways and do show these behaviors," says Sive, who is also a memberof the Whitehead Institute for Biomedical Research.

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