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Fish
cannot display symptoms of autism, schizophrenia or other human brain
disorders. However, a team of Massachusetts Institute of Technology (MIT)
biologists has shown that zebrafish can be a useful tool for studying the genes
that contribute to such disorders.
Led
by developmental biologist Hazel Sive, the researchers set out to explore a
group of about two dozen genes known to be either missing or duplicated in
about 1% 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.
The
findings should help researchers pinpoint genes for further study in mammals,
says Sive, a professor of biology and associate dean of MIT’s School of Science.
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.
“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.
Sive
and her colleagues described their findings a paper in an online edition of Disease
Models and Mechanisms. Lead authors of the paper are Whitehead postdoctoral
researchers Alicia Blaker-Lee, Sunny Gupta, and Jasmine McCammon.
A logical starting point
Sive recalls that some of her colleagues chuckled when she first proposed
studying human brain disorders in fish, but it is actually a logical starting
point, she says. Brain disorders are difficult to study because most of the
symptoms are behavioral, and the biological mechanisms behind those behaviors
are not well understood, she says.
“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,” she says.
Those
genes tend to be the same across species—conserved throughout evolution, from
fish to mice to humans—though they may control somewhat different outcomes in
each species.
In
the Disease Models and Mechanisms paper, Sive and her colleagues focused
on a genetic region known as 16p11.2, first identified by Mark Daly, a former
Whitehead researcher who identified a type of genetic defect known as a copy
number variant. A typical genome includes two copies of every gene, one from
each parent; copy number variants occur when one of those copies is deleted or
duplicated, and can be associated with pathology.
The “core” 16p11.2 region includes 25 genes. Both deletions and duplications in
this region have been associated with autism, but it was unclear which of the
genes might actually produce symptoms of the disease. “At the time, there was
an inkling about some of them, but very few,” Sive says.
Sive
and her postdoctoral researchers began by identifying zebrafish genes analogous
to the human genes found in this region. (In zebrafish, these genes are not
clustered in a single genetic chunk, but are scattered across many
chromosomes.) The researchers studied one gene at a time, silencing each with
short strands of nucleic acids that target a particular gene and prevent its
protein from being produced.
For
21 of the genes, silencing led to abnormal development. Most produced brain
deficits, including improper development of the brain or eyes, thinning of the
brain, or inflation of the brain ventricles, cavities that contain cerebrospinal
fluid. The researchers also found abnormalities in the wiring of axons, the
long neural projections that carry messages to other neurons, and in simple
behaviors of the fish. The results show that the 16p11.2 genes are very
important during brain development, helping to explain the connection between
this region and brain disorders.
Furthermore,
the researchers were able to restore normal development by treating the fish
with the human equivalents of the genes that had been repressed. “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,” Sive
says.
Genes with impact
To figure out which of these genes might have a strong effect in autism or
other disorders, the researchers set out to identify genes that produce
abnormal development when their activity is reduced by 50%, which would happen
in someone who is missing one copy of the gene. (This correlation is not seen
for most genes, because there are many other checks and balances that regulate
how much of a particular protein is made.)
The
researchers identified two such genes in the 16p11.2 region. One, called kif22,
codes for a protein involved in the separation of chromosomes during cell
division; another, aldolase a, is involved in glycolysis—the process of
breaking down sugar to generate energy for the cell.
Though
zebrafish have long been studied as a model of brain development, the new MIT
research adds a new dimension to their usefulness, says Su Guo, an associate
professor of pharmaceutical sciences at the University
of California at San Francisco.
“This
is really nice work that shows the importance of zebrafish in revealing disease
mechanisms related to human mental disorders—in this case, autism,” says Guo,
who was not involved in this study.
In
work that has just begun, Sive’s laboratory is working with Stanford University
researchers to explore in mice predictions made from the zebrafish study. They
are also doing molecular studies in zebrafish of the pathways affected by these
genes, to get a better idea of how defects in these might bring about
neurological disorders.
