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Brain riffs on immune system to generate neurological diversity

MosaicHave you ever wondered how our immune system generates the dizzying array of antibodies needed to recognize foreign invaders? They do so in part by using an ingenious combinatorial trick - a sleight of genetics that relies on the random rearrangement of discrete stretches of DNA to create as many as one trillion unique proteins to suss out and target for destruction all manner of nasty germs. The overall effect is somewhat like reorganizing the sentences in a paragraph or lines in a poem to tell an entirely different story (you've probably already seen it, but check out this poem that took over the internet a few weeks ago; it can be read from top or bottom), and it requires the presence of specific enzymes to first sever and then reconnect the DNA in a process called double-stranded break (or DSB) repair.

Now researchers from Harvard, including Frederick Alt, PhD, and Bjoern Schwer, MD, PhD, have suggested that stem cells in our brain may use a very similar method to generate neurological diversity specifically in genes responsible for synapse function and neural cell adhesion - affecting how nerves communicate with one another and their migration patterns during development. This may be an important way to generate what's known as somatic brain mosaicism, which is a complicated way to say that not all our brain cells are genetically identical. They published their results studying DSBs in neural stem and progenitor cells (NSPCs) late last week in Cell.

It's an enormously exciting finding, which Stanford stem cell researcher Irv Weissman, MD, together with Fred (Rusty) Gage, PhD, of the Salk Institute, summarize in an accompanying preview article in the same issue of the journal. Weissman and Gage write:

While much speculation and many experiments will follow this paper, it is now quite clear that, among the special cells that harbor high rates of localized DSBs, along with the immune B and T cells, one must now include the cells of the developing nervous system. One then wonders whether such DSBs, allowing neuronal diversification, are part of a necessary mechanism for individual identity.

It's not the first time that DSBs have been shown to be important in nervous system development. Previous research has shown that mice genetically engineered to lack the necessary repair enzymes are unable to make many neurons and die before birth. But the current study is the first to show that these breaks seem to be deliberately focused in specific cell types and genes. As Weissman and Gage explain:

Many of the identified genes are expressed in NSPCs located in the brain regions responsible for higher functions such as short-term learning, and mutations in these genes in humans are associated with (and maybe predispose to) psychiatric and neurological disorders manifested in mind functions—autism, manic depressive and depressive disorders, schizophrenia, and others. These experiments of nature, with the very clear mapping of the genes susceptible to DSBs, will likely be the beginning of a remarkably important set of future studies.

Previously: The making of a scientist — Stanford’s Irv Weissman under the Big Sky and Stanford researchers protest NIH funding restrictions 
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