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The Journal of Neuroscience, October 1, 2000, 20(19):7384-7393
Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6)
Deficiency Results in Exencephaly and Is Required for Apoptosis within
the Developing CNS
Mark A.
Lomaga1, 3,
Jeffrey T.
Henderson2,
Andrew J.
Elia3,
Jennifer
Robertson2,
Ryan S.
Noyce3,
Wen-Chen
Yeh3, 4, and
Tak W.
Mak1, 3, 4
1 Department of Pharmaceutical Sciences, Faculty of
Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2,
2 Samuel Lunenfeld Research Institute, Program in Molecular
Biology and Cancer, Mount Sinai Hospital, Toronto, Ontario, Canada M5G
1X5, 3 Amgen Institute, Toronto, Ontario, Canada M5G 2C1,
and 4 Ontario Cancer Institute and Departments of Medical
Biophysics and Immunology, University of Toronto, Ontario, Canada M5G
2M9
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.
Key words:
programmed cell death; TUNEL; CNS; thalamus; diencephalon; neural tube closure; gene targeting
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197384-10$05.00/0
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