Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures
Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures
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DOI：
10.1152/ajpcell.1999.276.4.c788
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发表时间：
1999-04-01
影响因子：
5.5
通讯作者：
Scott, WJ
中科院分区：
文献类型：
--
作者：
Bell, SM;Schreiner, CM;Scott, WJ
在大多数细胞中，普遍表达的Na+/H+交换异构体1 （NHE1）被认为是pH稳态、细胞体积调节和对生长因子刺激的增殖反应的主要调节剂。为了研究NHE1在胚胎发生过程中的功能，当这些细胞过程非常活跃时，我们通过用新霉素抗性基因替换编码跨膜结构域6和7的序列来靶向NHE1基因。对分离的腺泡细胞进行的NHE活性测定表明，目标等位基因在功能上是无效的。虽然NHE1的缺失与胚胎发育是相容的，但NHE1纯合突变体（-/-）在2周龄时表现出出生后生长速度的下降。此时，Nhe1 -/-动物也开始表现出共济失调和癫痫样发作。大约67%的-/-突变体在断奶前死亡。死后检查经常发现耳朵内、眼睛周围和下巴周围以及爪子的腹面有蜡状颗粒物质的堆积。成人组织的组织学分析显示胃固有层增厚，腺粘膜轻微萎缩。
In most cells, the ubiquitously expressed Na+/H+ exchanger isoform 1 (NHE1) is thought to be a primary regulator of pH homeostasis, cell volume regulation, and the proliferative response to growth factor stimulation. To study the function of NHE1 during embryogenesis when these cellular processes are very active, we targeted the Nhe1 gene by replacing the sequence encoding transmembrane domains 6 and 7 with the neomycin resistance gene. NHE activity assays on isolated acinar cells indicated that the targeted allele is functionally null. Although the absence of NHE1 is compatible with embryogenesis, Nhe1 homozygous mutants (-/-) exhibit a decreased rate of postnatal growth that is first evident at 2 wk of age. At this time, Nhe1 -/- animals also begin to exhibit ataxia and epileptic-like seizures. Approximately 67% of the -/- mutants die before weaning. Postmortem examinations frequently revealed an accumulation of a waxy particulate material inside the ears, around the eyes and chin, and on the ventral surface of the paws. Histological analysis of adult tissues revealed a thickening of the lamina propria and a slightly atrophic glandular mucosa in the stomach.