How does mutation of a protein involved in the response to DNA damage lead to defects in the nervous system? Reporting in Genes and Development, Peter McKinnon and co-workers describe a mechanism that might, they say, normally act during development to eliminate neural cells with genomic damage.

Several human syndromes with defective responses to DNA damage also lead to neurological lesions, and the best studied of these is the rare disorder ataxia-telangiectasia . Mutation of the protein responsible, the ATM kinase (reviewed by Kastan and Lim on page 179), results in progressive neurodegeneration. But how?

To find out, McKinnon and colleagues drew on their knowledge of DNA ligase IV (Lig4) — a molecular glue that binds double-stranded DNA breaks (DSBs), particularly during the process of V(D)J recombination. Mice with no functional Lig4 show widespread apoptosis in the developing nervous system, as well as embryonic lethality and defects in V(D) J recombination and lymphocyte development. The lack of Lig4 probably allows DSBs to accumulate and, given that ATM acts as a sensor for DSBs, the authors wondered whether these lesions might activate ATM (designated Atm in the mouse).

To answer this question they turned it on its head — if Atm is activated in response to a lack of Lig4, then might a lack of Atm rescue the Lig4-null phenotype? McKinnon and colleagues generated Atm−/−Lig4−/− double-knockout mice, and found that, in contrast to Lig4−/− single knockouts, these mice showed no apoptosis in the embryonic nervous system. Moreover, most of the processes required for correct neural development (as measured with markers for neuronal differentiation) were normal in the Atm−/−Lig4−/− mice. They were smaller than their wild-type littermates, however, and they also died roughly two days after birth.

The authors then tested whether the observed defects in the immune systems of Lig4−/− mice were rescued in the double knockouts. And they weren't — these animals showed T-cell defects and an almost complete lack of CD4+CD8+ thymocytes. McKinnon and co-workers believe that this result reflects the tissue-specific functionality of Atm, showing that the observed neuronal rescue is highly selective.

Plenty of questions remain. One is how these findings tie in with other studies showing that a lack of p53 also rescues the embryonic lethality in Lig4−/− mice, albeit to a differing degree (for example, p53−/−/Lig4−/− mice survive until six weeks of age). Another is whether other types of DNA lesion can trigger apoptosis in developing neurons, a possibility that seems very likely.

Finally, McKinnon and co-workers point out that it's remarkable how development can proceed so completely in the Atm−/− Lig4−/− mice — after all, their neurons must contain many unrepaired DSBs. Perhaps, then, it's no surprise that the mice die so soon after birth. And thinking about these results in the context of the human disease ataxia-telangiectasia, a lack of ATM probably allows cells with endogenously produced DSBs to become part of the nervous system. Subsequent malfunctioning owing to this genomic damage would then lead to the observed neurodegeneration.