Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 416insG mice
Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 416insG mice
复制标题
DOI：
10.1007/s00335-009-9235-0
复制
发表时间：
2010-02-01
期刊：
影响因子：
2.5
通讯作者：
Graw, Jochen
中科院分区：
文献类型：
--
作者：
Rosemann, Michael;Ivashkevich, Alesia;Graw, Jochen
一种新的自发小鼠突变体的特征是断奶时眼睑闭合且没有明显的眼睛（临时基因名称，eyeless；临时基因符号，eyl）。该突变遵循隐性遗传模式，并被定位到包含 Pitx3 的 19 号染色体区域。使用 Pitx3 (ak/+) 小鼠进行的基因互补测试证实 eyl 是 Pitx3 的新等位基因 (Pitx3 (eyl) )。对 eyl 突变体中的 Pitx3 基因进行测序，发现在 cDNA 位置 416（416insG；外显子 4）后插入了一个 G。预计移动的开放阅读框将产生仍含有 Pitx3 同源盒的杂合蛋白，但随后含有 121 个新氨基酸。新型 Pitx3 (eyl/eyl) 突变体表现出与 Pitx3 (ak/ak) 小鼠类似的眼科和大脑缺陷：小眼症或无眼症以及黑质多巴胺神经元的丧失。此外，我们在纯合无眼突变体中观察到脾脏中髓外造血作用增加，经常出现肝脏脂肪变性，并且体重减轻。纯合突变体还存在一些行为变化，包括前肢握力降低和伤害感受增加。除了两性的这些变化之外，我们还观察到雌性 Pitx3 (eyl/eyl) 小鼠的焦虑相关行为增加、运动活动减少、物体探索减少和社交接触增加；然而，我们观察到男性的焦虑相关行为减少，性唤起增加。在新的 Pitx3 突变中发现的大多数缺陷都在帕金森患者中观察到，这使得 Pitx3 (eyl) 突变体成为一个有价值的新模型。它是第一个在 Pitx3 编码区内携带点突变的小鼠突变体。
A new spontaneous mouse mutant was characterized by closed eyelids at weaning and without apparent eyes (provisional gene name, eyeless; provisional gene symbol, eyl). The mutation follows a recessive pattern of inheritance and was mapped to the region of chromosome 19 containing Pitx3. Genetic complementation tests using Pitx3 (ak/+) mice confirmed eyl as a new allele of Pitx3 (Pitx3 (eyl) ). Sequencing of the Pitx3 gene in eyl mutants identified an inserted G after cDNA position 416 (416insG; exon 4). The shifted open reading frame is predicted to result in a hybrid protein still containing the Pitx3 homeobox, but followed by 121 new amino acids. The novel Pitx3 (eyl/eyl) mutants expressed ophthalmological and brain defects similar to Pitx3 (ak/ak) mice: microphthalmia or anophthalmia and loss of dopamine neurons of the substantia nigra. In addition, we observed in the homozygous eyeless mutants increased extramedullary hematopoiesis in the spleen, frequently liver steatosis, and reduced body weight. There were also several behavioral changes in the homozygous mutants, including reduced forelimb grip strength and increased nociception. In addition to these alterations in both sexes, we observed in female Pitx3 (eyl/eyl) mice increased anxiety-related behavior, reduced locomotor activity, reduced object exploration, and increased social contacts; however, we observed decreased anxiety-related behavior and increased arousal in males. Most of these defects identified in the new Pitx3 mutation are observed in Parkinson patients, making the Pitx3 (eyl) mutant a valuable new model. It is the first mouse mutant carrying a point mutation within the coding region of Pitx3.