Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice
Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice
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DOI：
10.1073/pnas.052124799
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发表时间：
2002-04-16
影响因子：
11.1
通讯作者：
Rio, MC
中科院分区：
文献类型：
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作者：
Régnier, CH;Masson, R;Rio, MC
TRAF 4属于肿瘤坏死因子受体相关因子（TRAF）蛋白家族，但与其他家族成员不同，尚未明确与任何特定受体或信号通路相关。为了研究TRAM的生物学功能，我们通过基因破坏产生了traf 4缺陷小鼠。traN基因突变是胚胎致死的，但具有很大的个体差异，因为大约三分之一的纯合突变胚胎在胚胎第14天左右在子宫内死亡，而其他的则达到成年。存活的突变小鼠表现出许多发育异常;值得注意的是，100%的纯合子突变小鼠患有由气管环破坏引起的呼吸障碍和喘息。其他畸形主要涉及中轴骨骼，因为肋骨、胸骨、尾巴和椎弓受到影响，具有不同程度的扭曲。Traf 4缺陷小鼠也表现出脊柱裂的高发病率，这种缺陷类似于人类常见的先天性畸形神经管缺陷（NTD）。总之，我们的研究结果表明，TRAF 4是必需的胚胎发育过程中的关键生物过程，包括气管的形成，轴骨架的发展，和神经管的关闭。考虑到TRAF 4在神经组织中的正常表达模式，我们可以得出结论，TRAM参与体内神经形成。
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 TRAM, we have generated traf4-deficient mice by gene disruption. The traN 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 TRAM participates in neurulation in vivo.