Mark A. Lomaga* # Jeffrey T. Henderson* !, Andrew J. Elia #, Jennifer Robertson !, Ryan S. Noyce #, Wen-Chen Yeh#,4 & Tak W. Mak #

!  Samuel Lunenfeld Research Institute, Mount Sinai Hospital,
   Program in Molecular Biology and Cancer , 600 University Ave., Toronto, Ontario M5G-1X5
#  Amgen Institute, 620 University Avenue, suite 706, Toronto, Ontario, Canada M5G 2C1
* Authors contributed equally to this work.

Journal of Neuroscience, 20(19), 7382-93, 2000

Abstract

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. NT 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 immunohistochemical markers. In addition, relative levels of cellular proliferation and programmed cell death (PCD) were examined throughout embryonic development using bromodeoxyuridine (BrdU) and in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin 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 labeling 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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