Brain Building May Depend On DNA Cutting And Pasting

Immunologists' Discovery Could Lead to New Understanding of How the Nervous System Develops

Researchers at the Howard Hughes Medical Institute at Children's Hospital in Boston and the Center for Blood Research have made a discovery that could help solve one of the central riddles of biology-how the brain, with its dazzling display of cell types, develops from a relatively undistinguished pool of progenitor cells.

For years, immunologists have known that the immune system, with its multitude of T cells and antibodies, is produced not by a finite set of pre-existing genes but through a cutting and pasting of DNA fragments. This recombination process is carried out by a set of proteins that essentially snip genes into bits and then join the broken DNA ends, forming a nearly infinite supply of new genes. It now appears that two of these "paste" proteins are also required during a very specific period in brain development-when progenitor cells are developing into different kinds of neurons. The discovery, by a team led by Fred Alt, a Harvard Medical School professor of pediatrics at the Center for Blood Research and Children's, appears in the December 23 Cell.

"The exciting possibility is that there could be some program-gene rearrangement or something equivalent-that's occurring at a very specific time in brain development," says Alt, the Charles A. Janeway professor of pediatrics at HMS. "It may not be as complicated as putting whole sets of genes together as in the immune system. But one could imagine simpler things like molecular switches-DNA segments that are flipped or deleted to turn genes on and off in an irreversible fashion-which in turn could result in differentiation of progenitor nerve cells."

To arrive at their findings, Alt and his colleagues bred mice lacking genes for the two paste proteins, XRCC4 and ligase IV. In addition to severe immunological deficiencies, both strains of mice displayed holes

Contact: Peta Gillyatt
Harvard Medical School

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