ANALYSIS OF INSERTIONAL MUTATIONS IN TRANSGENIC MICE

在小鼠中，6号染色体上小眼畸形（mi）基因座的突变可能 导致异常，包括失去皮毛色素沉着，听力 损伤、小眼症和骨硬化症。这些异常导致 由于破骨细胞、视网膜色素细胞和神经细胞的缺乏， 皮肤和内耳的源于嵴的黑色素细胞。 使用转基因 在mi插入，我们最近分离出一个基因， 基因座，并编码一个新的成员的基本螺旋环螺旋拉链 一类转录因子。在迄今为止分析的所有mi等位基因中， 基因突变;在其中许多人中，突变的性质有助于 解释遗传模式和mi等位基因之间的相互作用 在复合杂合子中观察到的。 一 对该基因表达的详细分析表明， 在眼睛、内耳和 皮肤 为了更精确地理解mi是如何发挥其多效性的 在不同的细胞群上，我们已经建立了培养系统， 细胞增殖和分化可以在 结合Mi和其它基因的表达分析。突变 在mi可以作为模型的人Waardenburg综合征II型， 以听力变化为特征的遗传性综合征 损伤和色素改变。最近的分离和染色体 绘制人类的小鼠mi对应物MITF可能有助于阐明 这种疾病的分子基础和可能的其他形式的 综合征性听力损失 另一系转基因小鼠含有约15个转基因， 拷贝整合到小鼠mox 1基因的内含子中，该基因编码 中胚层同源结构域蛋白 这种转基因的纯合子小鼠 整合缺乏MOX 1表达，并显示出表征为 通过寰枕融合、半椎骨和短而弯曲的尾巴， 但它们能生育，寿命正常 与其他老鼠杂交 具有相似的表型，但在不同的基因突变，沿着， 详细研究mox 1和其他基因的表达，将有助于 将MOX 1放入参与基因组的遗传因素的层次结构中， 脊椎骨和头骨的发育。 Mox 1位于远端 11号染色体靠近尾短（Ts），这是一个基因座，其突变也是 与短而弯曲的尾巴有关。Ts和mox 1是否相同， 目前正在测试中。

In mice, mutations at the microphthalmia (mi) locus on chromosome 6 may lead to abnormalities that include loss of coat pigmentation, hearing impairment, microphthalmia, and osteopetrosis. These abnormalities result from deficiencies in osteoclasts, retinal pigment cells, and neural crest-derived melanocytes of the skin and inner ear. Using a transgenic insertion at mi, we have recently isolated a gene that resides at this locus and encodes a novel member of the basic-helix-loop-helix-zipper class of transcription factors. In all mi alleles analyzed to date, this gene is mutated; in many of them, the nature of the mutation helps explain the mode of inheritance and the interactions between mi alleles that have been observed previously in compound heterozygotes. A detailed analysis of the expression of this gene suggests that mi plays an important role early in melanocyte development in eye, inner ear, and skin. To understand more precisely how mi exerts its pleiotropic effect on different cell populations, we have established culture systems in which cell proliferation and differentiation can be studied in conjunction with analysis of expression of mi and other genes. Mutations at mi may serve as models for human Waardenburg syndrome type II, a hereditary syndrome characterized by varying degrees of hearing impairment and pigment alterations. The recent isolation and chromosomal mapping of the human counterpart of mouse mi, MITF, may help to clarify the molecular basis of this disorder and possibly other forms of syndromic hearing loss. Another line of transgenic mice contains approximately 15 transgene copies integrated into an intron of the mouse mox1 gene that encodes a mesodermal homeodomain protein. Mice homozygous for this transgene integration lack expression of mox1 and show a phenotype characterized by atlanto-baso-occipital fusions, hemivertebrae, and short, kinky tails, but they are fertile and have a normal lifespan. Crosses with other mice with similar phenotypes but mutations in different genes, along with a detailed study of the expression of mox1 and other genes, will help to place mox1 into a genetic hierarchy of factors involved in the development of the vertebra and skull. Mox1 is localized on distal chromosome 11 near Tail short (Ts), a locus whose mutations are also associated with short, kinky tails. Whether Ts and mox1 are identical is currently being tested.