Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) regulates axon integrity in the mouse embryo.
Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) regulates axon integrity in the mouse embryo.
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烟酰胺单核苷酸腺苷转移酶2（NMNAT2）调节小鼠胚胎中的轴突完整性。
DOI：
10.1371/journal.pone.0047869
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bishop CE
中科院分区：
文献类型：
--
作者：
Hicks AN;Lorenzetti D;Gilley J;Lu B;Andersson KE;Miligan C;Overbeek PA;Oppenheim R;Bishop CE
利用转座子介导的基因诱变，我们产生了一种新的小鼠突变体，名为Blad(膀胱肿胀)。纯合子突变小鼠在围产期死亡，表现为膀胱严重膨胀，横隔膜发育不良，骨骼肌总质量减少。野生型和杂合子小鼠表现正常。通过聚合酶链式反应，我们在Nmnat2(烟酰胺单核苷酸腺苷转移酶2)的第一内含子上发现了一个转座子插入位点。Nmnat2主要在大脑和神经系统中表达，并与轴突的生存有关。在Nmnat2blad/blad突变体中未检测到该基因的表达。对E18.5Nmnat2blad/blad突变胚脑的检查没有发现任何明显的形态变化。相比之下，E18.5Nmnat2blad/blad纯合子显示腰部脊髓运动神经元减少约60%，背根神经节(DRG)感觉神经元减少80%以上。此外，面部运动神经元数量严重减少，后肢几乎完全没有轴突。我们的观察表明，在胚胎发育过程中，Nmnat2在轴突的生长或维持中起着重要的作用。似乎在缺少Nmnat2的情况下，主要的靶器官和组织(例如肌肉)没有得到功能上的神经支配，从而导致围产期死亡。此外，Nmnat1和3都不能补偿Nmnat2的损失。虽然最近有人认为Nmnat2可能是轴突完整性的内源性调节剂，但这项工作是第一次活体研究表明Nmnat2参与哺乳动物的轴突发育或生存。
Using transposon-mediated gene-trap mutagenesis, we have generated a novel mouse mutant termed Blad (Bloated Bladder). Homozygous mutant mice die perinatally showing a greatly distended bladder, underdeveloped diaphragm and a reduction in total skeletal muscle mass. Wild type and heterozygote mice appear normal. Using PCR, we identified a transposon insertion site in the first intron of Nmnat2 (Nicotinamide mononucleotide adenyltransferase 2). Nmnat2 is expressed predominantly in the brain and nervous system and has been linked to the survival of axons. Expression of this gene is undetectable in Nmnat2blad/blad mutants. Examination of the brains of E18.5 Nmnat2blad/blad mutant embryos did not reveal any obvious morphological changes. In contrast, E18.5 Nmnat2blad/blad homozygotes showed an approximate 60% reduction of spinal motoneurons in the lumbar region and a more than 80% reduction in the sensory neurons of the dorsal root ganglion (DRG). In addition, facial motoneuron numbers were severely reduced, and there was virtually a complete absence of axons in the hind limb. Our observations suggest that during embryogenesis, Nmnat2 plays an important role in axonal growth or maintenance. It appears that in the absence of Nmnat2, major target organs and tissues (e.g., muscle) are not functionally innervated resulting in perinatal lethality. In addition, neither Nmnat1 nor 3 can compensate for the loss of Nmnat2. Whilst there have been recent suggestions that Nmnat2 may be an endogenous modulator of axon integrity, this work represents the first in vivo study demonstrating that Nmnat2 is involved in axon development or survival in a mammal.
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