|
Zebrafish turn the tide in autism research
August 2012
EDIT CONNECT
SHARING OPTIONS:
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.
Code: E081218 Back |
Home |
FAQs |
Search |
Submit News Release |
Site Map |
About Us |
Advertising |
Resources |
Contact Us |
Terms & Conditions |
Privacy Policy
|