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Stem cell Asymmetric division Committed progenitor Disrupted Ku70, Ku80, DNA ligase IV, XRCC4, nibrin
DNA damage
Self-renewal
Disrupted ATM and/or p53, combined with disrupted Ku70, Ku80, DNA ligase IV or nibrin
DNA damage
Symmetric proliferation
Clearance
ATM p53
Cell cycle exit, differentiation Extensive neuronal death, microcephaly with developmental defects Minimal developmental defects, progressive neurodegeneration
Katherine Ris
Figure 1 DNA damage in the brain during development and in the adult. During development, neural stem cells undergo asymmetric division to generate a self-renewing cell and a committed neural progenitor cell. These neural progenitors proliferate in specific areas of the fetal and adult brain. An unknown trigger then signals the cells to exit the cell cycle and initiate the process of differentiation. In the absence of DNA repair proteins (e.g., Ku70, Ku80, DNA ligase IV, XRCC4 and nibrin), increased numbers of cells with chromosomal instability are generated6,8,9. Such cells are cleared by apoptosis through an ATM- and p53-dependent mechanism7,10,12such cell clearance seems to underlie several neurological disorders. In the absence of ATM or with diminished levels of p53, cells with severe genomic instability are not cleared and differentiate into neurons. These abnormal cells then contribute to the development of the brain1,5,7,8,10,12, as shown by Frappart et al. in a mouse model of NBS. The manifestions of disturbances in either pathway in the nervous system range from hypoplasia of brain structures and microcephaly associated with mental retardation to progressive neurodegeneration.
The authors are at BrainCells Inc., San Diego, California 92121, USA. e-mail: cbarlow@braincellsinc.com
and to arrest the cell cycle. The discovery of the gene and subsequent work established a clear link between a protein that repairs DNA and defects in the nervous system. Subsequent studies showed that several proteins, including nibrin, interact directly with ATM, and facilitate its activity. Understanding this complex system
in the brain has been greatly facilitated by several mouse models with targeted mutations in DNA repair genes, as well as the gene encoding p53 the key regulator of the cell cycle and apoptosis machinery and an ATM target. One of the earliest genetic mouse models was for ataxia telangiectasia, followed quickly
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Blood vessels were originally envisaged as a passive barrier. They themselves did not promote blood clottingand their only role in inflammation was to facilitate trafficking of leukocytes at sites of infection. Recent studies have identified a number of molecules on the endothelial cells lining blood vessels that actively regulate both of these complex processes. One such molecule is thrombomodulin. Found mainly on the
The author is at the Howard Hughes Medical Institute at the Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA. e-mail: Charles-Esmon@omrf.ouhsc.edu
surface of vascular endothelium, it interacts with multiple proteins to block blood clotting and inhibit inflammation. In a recent issue of the Journal of Clinical Investigation, Abeyama et al.1 find another partner for thrombomodulin. They report that thrombomodulin binds and inhibits high mobility group box 1 protein (HMGB1), a molecule with potent cytokine-like activity. HMGB1 appears to contribute to late-stage inflammatory disease like sepsis, so there has been intense interest in finding ways to stop it by identifying negative regulators. The new work brings one such regulator to light. Much of the research on thrombomodulin has focused on the domains responsible for the
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