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THE secret to wiring the brain might be a protein that comes in tens of
thousands of different forms.

As the brain develops, over a trillion neurons send out fibres called axons
to link to distant neurons, guided by chemical signals from neighbouring cells.
Relatively few guidance molecules are known, so it鈥檚 hard to understand how all
these neurons manage to make precise connections. That鈥檚 why the discovery of a
receptor on fruit fly neurons that comes in many thousands of different forms
has excited scientists, who think its numerous 鈥渇lavours鈥� could play a crucial
role in the way axons respond to signals from other cells.

The researchers, at the University of California at Los Angeles and the
University of Michigan in Ann Arbor, had been studying two intracellular
proteins that fruit flies need for their axons to grow properly. They found that
one of these proteins interacts with a receptor on the surface of neurons that
looks very similar to a human receptor protein called Dscam.

So they began to search through the fruit fly genome for a more exact match
for the human gene. But instead of finding it, they discovered that the fruit
fly Dscam gene sequence could produce more than 38 000 different
protein variants. 鈥淚t was a complete surprise,鈥� says Dietmar Schmucker, a member
of the research team.

A single gene can produce many variants thanks to a process called
alternative splicing. The coding portions of a gene are often interrupted by
long stretches of DNA with no apparent function. These non-coding regions
have to be cut out and the coding regions spliced together when the cell makes
the messenger RNA that serves as a blueprint for the cell鈥檚 protein factory.

There can be several alternative versions of a coding region, and by using
one alternative rather than another, different forms of a protein can be generated
(see Diagram).
Dscam has 24 coding regions, and four of these
have multiple alternatives鈥攁s many as 48 in one case鈥攖hat the cell
can choose from when splicing RNA.

Many other proteins vary because of alternative splicing, but previously no
more than about a thousand different forms had been discovered for any one gene.
Fruit fly Dscam seems to be the record holder, says Douglas Black, an
alternative splicing expert also at UCLA. Studies of fly embryos revealed that
different types of Dscam are made during development, and that the Dscam
receptor is essential for proper neural development. 鈥淲hat these individual
splice variants might be doing is potentially very interesting,鈥� says Black.

鈥淚t鈥檚 a very exciting discovery,鈥� agrees Corey Goodman, an expert in axon
guidance at the University of California at Berkeley. 鈥淎re they all generated,
and what do they do? We don鈥檛 know, but it鈥檚 certainly intriguing.鈥�