Rearranging Views on Neurogenesis Neuronal Death in the Absence of DNA End-Joining Proteins

somal break can be a lethal event for a cell. present results from the most recent of several related studies that have used gene " knockout " strategies in New Haven, Connecticut 06520 mice to produce null mutations in genes involved in NHEJ. The principal gene analyzed in the paper, XRCC4, was first identified based on its ability to complement Embryonic neurogenesis in mammals occurs over a dis-a mutant cell line defective in V(D)J recombination and crete developmental period from which many different DNA DSBR (Li et al., 1995). It was, therefore, not surpris-neuronal types arise. In the central nervous system (CNS), ing that XRCC4-deficient mice were defective in V(D)J newly postmitotic neurons are " born " in an anatomically recombination (with a corresponding block in lympho-defined proliferative region overlying the ventricles, as cyte development) and hypersensitive to ionizing radia-epitomized in the cerebral cortex by the ventricular zone tion (Gao et al., 1998). However, unlike the deletion of (VZ; Figure 1A). After birth, a newly postmitotic neuron migrates superficially through the intermediate zone (IZ) to locate in the future cortical gray matter, the cortical plate (CP). Three general processes occur among em-bryonic blasts within the VZ: cell proliferation, differentiation , and death. The general molecular mechanisms thus far described for these cellular fates have not been vastly different from those occurring in other proliferating epithelia, including important roles for growth factors , transcription factors, and cell death molecules. This poses the question of how and when the vast extent of neuronal heterogeneity arises from the VZ. Is there a distinguishing mechanism to account for this, and might it involve a genetic generator of diversity that breaks and reconfigures chromosomes, in a manner analogous to the V(D)J recombination reaction used by lympho-cytes to generate diverse antigen receptors? A provocative , recent study from the Alt laboratory (Gao et al., 1998) suggests that chromosomal breaks may indeed be generated and repaired at a specific stage of neuro-genesis, around the point where neurons become post-mitotic in the VZ but before reaching the CP. The evidence: two DNA double strand break repair (DSBR) proteins that are critical for V(D)J recombination are also involved in the survival of neurons arising from the VZ. Here, we discuss the implications of this intriguing finding in the context of what is known about recombination Figure 1. Cell Death in the Embryonic Cerebral Cortex in lymphocytes, the DSBR machinery, …