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Tumor necrosis factor receptor-associated factor 6 (TRAF6) deficiency results in exencephaly and is required for apoptosis within the developing CNS

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2000; 20(19):7384-93.
Source: PubMed

ABSTRACT Tumor necrosis factor receptor-associated factors (TRAFs) are adaptor proteins important in mediating intracellular signaling. We report here that targeted deletion of traf6 greatly increases the frequency of failure of neural tube closure and exencephaly in traf6 (-/-) mice. The penetrance of this defect is influenced by genetic background. Neural tube fusion requires the coordination of several biological processes, including cell migration invoked by contact-dependent signaling, cell proliferation, and programmed cell death (PCD). To gain greater insight into the role of TRAF6 in these processes, neural development and migration within the CNS of traf6 (-/-) mice and controls were assessed through temporal examination of a number of immunohistochemical markers. In addition, relative levels of cellular proliferation and PCD were examined throughout embryonic development using bromodeoxyuridine (BrdU) and in situ terminal deoxynucleotidyl transferase-mediated dUTP biotinylated nick end labeling (TUNEL), respectively. The data suggest that loss of TRAF6 does not significantly alter the level of cellular proliferation or the pattern of neural differentiation per se, but rather regulates the level of PCD within specific regions of the developing CNS. Substantial reductions in TUNEL were observed within the ventral diencephalon and mesencephalon in exencephalic traf6 (-/-) embryos. Our results demonstrate a novel and prominent role for TRAF6 in the regional control of PCD within the developing CNS.

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    • "Notes contained in blue boxes relate to positive relationships, notes in red boxes relate to inverse or negative relationships. 1 Denny et al. (2013). 2 Girardi et al. (2008). 3 Lomaga et al. (2000); McGrath et al. (1999); McLin et al. (2008); Phelan et al. (2005); Regnier et al. (2002); Tissir et al. (2004). 4 Torchinsky et al. (1997); Hrubec et al. (2006). "
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    • "In TRAF6 -/mice , an increase in the frequency of impaired neural tube closure and exencephaly has been found, suggesting that TRAF6 may regulate the levels of programmed cell death within specific regions of the developing CNS (Lomaga et al., 2000). In primary astrocytes stimulated with beta-amyloid, TRAF6 inhibition prevents reactive gliosis and iNOS expression (Akama & Van Eldik, 2000). "
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