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Tumor necrosis factor receptor-associated factor 6 (TRAF6) deficiency results in exencephaly and is required for
M A Lomaga1, J T Henderson, A J Elia
1Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
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.
Insights
Loss of Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) in mice leads to neural tube defects, specifically exencephaly. TRAF6 regulates programmed cell death in the developing central nervous system, impacting neural tube closure.
Area of Science:
- Developmental Biology
- Neuroscience
- Immunology
Background:
- Tumor Necrosis Factor Receptor-Associated Factors (TRAFs) are critical adaptor proteins in intracellular signaling pathways.
- TRAF6 plays a role in various cellular processes, including immune responses and development.
Purpose of the Study:
- To investigate the role of TRAF6 in neural tube development and closure.
- To determine how TRAF6 deficiency affects cellular proliferation, differentiation, and programmed cell death (PCD) in the developing central nervous system (CNS).
Main Methods:
- Generation and analysis of traf6 (-/-) knockout mice to study neural tube defects.
- Immunohistochemical analysis of CNS development and migration markers.
- Assessment of cellular proliferation using bromodeoxyuridine (BrdU) incorporation.
- Quantification of programmed cell death (PCD) using in situ terminal deoxynucleotidyl transferase-mediated dUTP biotinylated nick end labeling (TUNEL) assay.
Main Results:
- Targeted deletion of traf6 significantly increases the incidence of neural tube closure failure and exencephaly in mice.
- Loss of TRAF6 does not substantially alter cellular proliferation or neural differentiation patterns.
- TRAF6 deficiency leads to reduced programmed cell death (PCD) in specific regions of the developing CNS, including the ventral diencephalon and mesencephalon.
Conclusions:
- TRAF6 is essential for proper neural tube closure during embryonic development.
- TRAF6 plays a crucial role in the regional regulation of programmed cell death (PCD) within the developing CNS.
- Dysregulation of TRAF6-mediated PCD contributes to neural tube defects like exencephaly.