Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice.
TRAF4 belongs to the tumor necrosis factor receptor-associated factor (TRAF) family of proteins but, unlike other family members, has not yet been clearly associated to any specific receptor or signaling pathway. To investigate the biological function of TRAF4, we have generated traf4-deficient mice by gene disruption. The traf4 gene mutation is embryonic lethal but with great individual variation, as approximately one third of the homozygous mutant embryos died in utero around embryonic day 14, whereas the others reach adulthood. Surviving mutant mice manifest numerous developmental abnormalities; notably, 100% of homozygous mutant mice suffer respiratory disorder and wheezing caused by tracheal ring disruption. Additional malformations concern mainly the axial skeleton, as the ribs, sternum, tail, and vertebral arches are affected, with various degrees of penetrance. Traf4-deficient mice also exhibit a high incidence of spina bifida, a defect likened to neural tube defects (NTD) that are common congenital malformations in humans. Altogether, our results demonstrate that TRAF4 is required during embryogenesis in key biological processes including the formation of the trachea, the development of the axial skeleton, and the closure of the neural tube. Considering the normal expression pattern of TRAF4 in neural tissues, we can conclude that TRAF4 participates in neurulation in vivo.
Régnier
Catherine H
CH
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Propre de Recherche 6520/Institut National de la Santé et de la Recherche Médicale Unité 184/Université Louis Pasteur, Illkirch, France.
Masson
Régis
R
Kedinger
Valérie
V
Textoris
Julien
J
Stoll
Isabelle
I
Chenard
Marie-Pierre
MP
Dierich
Andrée
A
Tomasetto
Catherine
C
Rio
Marie-Christine
MC
D000818:Animals; D015153:Blotting, Western; D001842:Bone and Bones / Q000002:abnormalities*; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D006720:Homozygote; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009432:Neural Crest / Q000002:abnormalities* / Q000196:embryology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D016135:Spinal Dysraphism / Q000235:genetics; D053449:TNF Receptor-Associated Factor 4; D014132:Trachea / Q000002:abnormalities*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
D018076:DNA, Complementary; D011506:Proteins; D053449:TNF Receptor-Associated Factor 4; C506368:Traf4 protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins