|Flies for kids: developing a genetic model for the neuropathology and behavioral deficits in Fragile X
By Bassem Hassan, 3/1/2004
June 2005: Fruit fly helps reveal the secrets of Fragile X
Since 1991, scientists have known that a defect in one gene causes
Fragile X. This defect causes the FMRP protein (named for "Fragile X mental retardation protein")
to lose its function. However, up to now, it has not been clear which
bodily reactions are blocked by the loss of function of this one gene, given the fact that FMRP
controls many other genes as well.
Research on fruit flies
Bassem Hassan's group studies Fragile X using fruit flies because they contain
the dFMRP protein, which is analogous to the human FMRP protein. Like humans with
Fragile X, fruit flies in which the dFMRP gene has been knocked out display behavior problems and disturbances
in the brain.
Actin and profilin
Their research has led to the discovery that fruit flies that produce no dFMRP in turn produce more profilin.
Profilin, a protein, regulates the dynamics of actin, which has a very important function regarding the form
and structure of all types of cells, including neurons. Actin acts as a kind of scaffolding that supports the
cell and gives it shape. Too much profilin disturbs the regulation of actin, resulting in abnormal neuron
sub-divisions. The researchers found this in the fruit flies that produce no dFMRP.
A new interaction revealed
Bassem Hassan and his group (Simon Reeve, Laura Bassetto, and Maarten Leyssen) are the first to demonstrate
that dFMRP controls regulation of the actin skeleton in fruit flies that produce no dFMRP. In these flies,
this entire process goes awry and the neurons no longer form the correct patterns. This is probably also the
case for humans, and so this research can lead to a better understanding of Fragile X and brain development.
The researchers now propose to study this result in mice models of Fragile X.
These mammals, of course, are a rung closer to humans on the evolution ladder.
By Bassem Hassan, 3/2004
In our lab we use the fruit fly, which has proven a powerful
tool for unravelling genetic mechanisms. Fruit flies
have a single copy of the Fragile X gene, called dFMR1.
The fly dFMR1 protein, as with the human protein, is
known to interact with other proteins and mRNAs (the
intermediate between DNA and protein).
Children with Fragile X display behavioral impairments
and anatomical defects in how neurons (brain cells) connect
to each other. We have already shown that flies lacking
the dfmr1 gene show behavioral and anatomical
defects in their brains. How do these defects occur? The
Fragile X protein appears to play a major role in controlling
the expression of other genes -- many other genes!
How, then, can we tell which of these genes are most
important in causing the brain defects?
To tackle this question, we checked all genes in flies for
the sequences to which the dFMR1 protein binds. We
found around 260 such genes. Next we asked which of
these genes are not correctly regulated in mutant flies. We
found that genes which regulate the shape of cells,
cytoskeleton genes, were most consistently affected. Next,
we asked if playing with the amounts of these cytoskeletal
proteins and the amount of dFMR1 could prove a functional
relationship between the two. This was the case. It
appears that the major problem in the brains of Fragile X
flies, and perhaps in the brains of patients as well, is that
genes which give neurons their shape and control their
connectivity are not present in the right amounts.
The key now is to understand the relationship between the
misregulated genes, the defects we see in brain cells, and
the behavioral problems of the Fragile X flies. To do that,
we have to be able to switch the dFMR1 gene off and back
on whenever and wherever we want and ask which brain
cells need this protein and when do they need it for normal
development and behavior. Using a new trick called
transgenic RNAi, we are testing the requirements for
dFMR1 in different neurons at different times and should
be able to correlate the genetics with the anatomy and the
behavior to paint a detailed picture of how this one gene
can have such dramatic effects on brain development.