Mice deficient for testis-brain RNA-binding protein exhibit a coordinate loss of TRAX, reduced fertility, altered gene expression in the brain, and behavioral changes
Mice deficient for testis-brain RNA-binding protein exhibit a coordinate loss of TRAX, reduced fertility, altered gene expression in the brain, and behavioral changes
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DOI：
10.1128/mcb.23.18.6419-6434.2003
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发表时间：
2003-09-01
影响因子：
5.3
通讯作者：
Hecht, NB
中科院分区：
文献类型：
--
作者：
Chennathukuzhi, V;Stein, JM;Hecht, NB
睾丸-脑RNA结合蛋白(TB-RBP)是一种广泛表达和高度保守的蛋白质，与人类Translin蛋白同源，在染色体易位、有丝分裂细胞分裂以及mRNA运输和储存中具有重要作用。为了更好地确定TB-RBP的生物学作用，我们培育了缺乏TB-RBP的小鼠。杂合子之间的配对在正常的孟德尔比例下产生了可存活的、表面上正常的纯合子突变小鼠。Tb-RBP相关和相互作用蛋白Translin相关因子X在杂合子中降低到50%的正常水平，而在Tb-RBP缺失的动物中缺失。空白小鼠出生时比它们的野生型或杂合子小10%到30%，并一直保持到大约6到9个月大，显示出正常的B细胞和T细胞发育，并积累内脏脂肪。TB-RBP-nulI雄性小鼠具有生育能力，并产生了后代，但生精小管异常，精子数量减少。无生育能力的雌性小鼠生育能力较差，且产仔数减少。对缺失型和野生型小鼠脑总RNA的微阵列分析显示，在12,473个探针组中，有14个基因上调，217个基因下调，基因表达谱发生了变化。许多神经递质受体和离子通道，包括γ-氨基丁酸A受体α1和谷氨酸受体α3，被强烈下调。还发现了行为异常。与同窝小鼠相比，TB-RBP基因缺失的小鼠看起来很温顺，表现出较低的Rota-Rod表现。
Testis-brain RNA-binding protein (TB-RBP), the mouse orthologue of the human protein Translin, is a widely expressed and highly conserved protein with proposed functions in chromosomal translocations, mitotic cell division, and mRNA transport and storage. To better define the biological roles of TB-RBP, we generated mice lacking TB-RBP. Matings between heterozygotes gave rise to viable, apparently normal homozygous mutant mice at a normal Mendelian ratio. The TB-RBP-related and -interacting protein Translin-associated factor X was reduced to 50% normal levels in heterozygotes and was absent in TB-RBP-null animals. The null mice were 10 to 30% smaller than their wild-type or heterozygote littermates at birth and remained so to about 6 to 9 months of age, showed normal B- and T-cell development, and accumulated visceral fat. TB-RBP-nulI male mice were fertile and sired offspring but had abnormal seminiferous tubules and reduced sperm counts. Null female mice were subfertile and had reduced litter sizes. Microarray analysis of total brain RNA from null and wild-type mice revealed an altered gene expression profile with the up-regulation of 14 genes and the down-regulation of 217 genes out of 12,473 probe sets. Numerous neurotransmitter receptors and ion channels, including gamma-aminobutyric acid A receptor alpha1 and glutamate receptor alpha3, were strongly down-regulated. Behavioral abnormalities were also seen. Compared to littermates, the TB-RBP-null mice appeared docile and exhibited reduced Rota-Rod performance.