Zebrafish Used In Autism Research

Connie K. Ho for redOrbit.com

Apes and humans are thought to be intertwined in evolutionary theory, but how about fish and humans? A new study utilized zebrafish in a study regarding human brain disorders. In particular, Massachusetts Institute of Technology (MIT) researchers recently revealed that they took a fresh approach to understanding the roles of genes linked to autism and demonstrated how zebrafish could be utilized in examining the genes that contribute to human brain disorders.

The group of researchers was led by developmental biologist Hazel Sive in studying around two dozen genes that were identified as missing or duplicated in around one percent of autistic patients. While most of the genes´ functions were not known, the MIT study showed that almost all of them led to brain abnormalities when eliminated from zebrafish embryos. The results of the study should help investigators determine genes for future study of mammals. Since autism is thought to be the result of a number of genetic defects, the research is part of a larger effort to determine culprit genes and create treatments that can work focus on those genes.

“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,” remarked Sive, a professor biology and associate dean of MIT´s School of Science, in a prepared statement.

Sive believes that brain disorders are not necessarily easy to study as symptoms are behavioral and the biological mechanisms propelling those behaviors are not studied often. She describes genes as similar across species, conserved throughout evolution even though they may control different outcomes in different species. Sive and colleagues looked at a genetic region called 16p11.2, a region whose “core” includes 25 genes.

“We thought that since we really know so little, that a good place to start would be with the genes that confer risk in humans to various mental health disorders, and to study these various genes in a system where they can readily be studied,” explained Sive in the statement.

In the region 16p11.2, deletions and duplications in the region have been linked to autism but it´s been unclear as to which genes created symptoms of the disease.

“At the time, there was an inkling about some of them, but very few,” noted Sive in the statement.

As such, Sive and other researchers began looking at zebrafish genes that were analogous to the human genes found in region 16p11.2. They examined one gene at a time, using short strands of nucleic acids to silence genes that focused on a particular gene and prevented its protein from being created. As such, silencing caused abnormal development for 21 of the genes. Many created brain deficits, such as improved development of the brain or eyes, thinning of the brain, or inflation of the brain ventricles. Abnormalities in the wiring of axons, which carried messages to other neurons, were also discovered. The researchers concluded that the 16p11.2 genes were crucial to brain development and gained a better understanding of the association between the region and brain disorders. The team was able to restore normal development for the fish with treatments of human equivalents of the genes that had been silenced.

“That allows you to deduce that what you´re learning in fish corresponds to what that gene is doing in humans. The human gene and the fish gene are very similar,” commented Sive in the statement.

Through the research results, the group determined two genes that had a strong effect in autism and other brain disorders. They looked at genes that led to abnormal development when their activity was reduced in half. One of the genes, kif22, coded for proteins that participated in the separation of chromosomes for cell division. Another gene, adolase a, participated in gylcolysis, which breaks down sugar to create energy for the cell.

“This is really nice work that shows the importance of zebrafish in revealing disease mechanisms related to human mental disorders – in this case, autism,” mentioned Su Guo, an associate professor of pharmaceutical sciences at the University of California at San Francisco who´s unaffiliated in the study, in the statement.

The research is published in a recent paper in the online edition of the journal Disease Models and Mechanisms.

Image 2 (below): Zebrafish with certain genes turned off during embryonic development (center and right images) showed abnormalities of brain formation (top row) and axon wiring (bottom row). At left is a normally developing zebrafish embryo. Image: Sive Lab