Brain wiring depends on multifaceted gene

For those who struggle to assemble a bike on Christmas Eve or wrestle in vain with the wiring of a home theater system, consider the daunting task that faces the developing human brain. It must make sure that its billions of nerve cells correctly establish trillions of connections among themselves.

Scientists studying how the growing brain of the fruit fly performs its slightly less complex version of this task have found a new gene with a role in guiding growing nerve fibers. This discovery, described in the June 9 Cell by S. Lawrence Zipursky of the Howard Hughes Medical Institute at the University of California, Los Angeles and his colleagues, has grabbed the attention of neuroscientists for two reasons.

First, the human version of the gene may play a role in Down’s syndrome, a form of mental retardation that results from having an extra copy of chromosome 21. Second, the fly gene appears capable of producing more than 38,000 distinct proteins, an extraordinary diversity that could help explain how the developing brain creates order out of its chaos of nerve fibers.

“It’s a lovely piece of work,” says Marc Tessier-Lavigne of University of California, San Francisco. “It’ll be interesting to know to what extent this potential for diversity is actually used in the nervous system.” Both Tessier-Lavigne and Zipursky study a process called axon guidance. Researchers have discovered a handful of chemical signals in the developing brain that direct axons, the fibers that nerve cells extend to each other. The novel gene identified by Zipursky’s team appears to encode an axonal surface protein, or receptor, that responds to such guidance molecules.

Zipursky and his colleagues unearthed this receptor while looking for the cell-surface partner that teams up with two previously identified proteins inside axons. These proteins were known to respond to guidance signals from the outside. Using one of the proteins as bait, the team fished for molecules that bind to it and landed the receptor.

Unexpectedly, the receptor’s gene looked like a fly version of a previously identified human gene that encodes a nerve cell-surface protein. The gene resides on chromosome 21 in people, and the mouse version is active in the developing rodent brain, Julie R. Korenberg of the Cedars-Sinai Research Institute in Los Angeles and her colleagues reported in 1998. From those clues, her team suggested that having an extra copy of the gene contributes to the neurological problems observed in Down’s syndrome. They named the gene’s protein DSCAM, for Down’s syndrome cell adhesion molecule.

Zipursky’s team confirmed that this fly gene is active in the developing insect brain and discovered that fly embryos with mutations in the gene die at the larval stage. By studying the mutant embryos, the investigators observed that axon guidance went awry in these insects. In particular, axons from a well-studied fly nerve frequently missed their target.

On the basis of the gene’s DNA sequence and structure, the investigators also suspected that the gene for the fly protein, by convention dubbed Dscam, would undergo alternative splicing. In this process, a cell reads the DNA of a single gene in different ways to create various forms of messenger RNA (mRNA), which the cell uses to construct subtly distinct proteins.

In fact, Zipursky’s team concluded that the gene could create more than 38,000 versions of Dscam, each consisting of a slightly different string of amino acids. To address this possibility, the scientists randomly isolated 50 mRNA strands from the gene in the developing fly brain and determined that these mRNAs would have produced 49 versions of Dscam. That suggests that the fly brain indeed uses all of the protein’s possible forms, Zipursky’s team concludes.

Even as neuroscientists continue to probe the role of the gene for Dscam in other species, notes Tessier-Lavigne, they’re racing to identify the axon-guidance signals to which the receptor responds.