MESODERMAL HOMEODOMAIN PROTEIN DURING VERTEBRAL DEVELOPMENT

椎骨发育过程中的中胚层同源域蛋白

• 批准号: 6163105
• 负责人: H ARNHEITER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6163105
• 关键词: DNA binding protein; artificial chromosomes; developmental neurobiology; gene deletion mutation; gene expression; gene rearrangement; genetically modified animals; laboratory mouse; mesoderm; phenotype; transcription factor; transposon /insertion element; vertebrae

Mice with a transgenic insertional mutation in the Meox1 mesodermal homeodomain transcription factor gene on chromosome 11 show abnormalities in the axial skeleton including cranio-vertebral fusions, vertebro- vertebral fusions, hemivertebrae, and a vertebrogenic spina bifida. These phenotypes can all be traced back to abnormalities in the developing sklerotome. A close relative, Meox2, though initially coexpressed with Meox1, evidently cannot compensate for the lack of Meox1. However, even though the lack of Meox2 alone is compatible with life, mice doubly homozygous for our Meox1 allele and a Meox2 knock-out allele are severely affected as demonstrated in a collaborative effort. Thus, Meox1 and Meox2 are two related mesodermal homeodomain transcription factors that must collaborate to establish the intricate patterning of the axial skeleton. Interestingly, homozygous Meox1 mutant females cannot lactate because of a defect in mammary gland development during late pregnancy. Whether this lactation defect is due to a stromal or an epithelial defect is currently being investigated by mammary gland transplantations. Since the transgenic insertion has resulted in a deletion of genomic DNA beyond the 3' end of the Meox1 gene, it is possible that the skeletal phenotype and/or the mammary gland phenotype are due to effects on one or more than one additional gene located in the vicinity of Meox1. Therefore, we have initiated attempts to rescue the mutant mice with a Meox1 cDNA, using a YAC-based transgenic strategy.

Meox 1中胚层转基因插入突变小鼠 11号染色体上同源结构域转录因子基因显示异常 在中轴骨骼中，包括颅-椎骨融合，椎骨- 椎骨融合半椎骨和脊椎源性脊柱裂 这些 表型都可以追溯到发育中的异常， 骨刀 一个近亲，Meox 2，虽然最初与 Meox 1显然不能弥补Meox 1的缺乏。 但即使 尽管缺乏Meox 2本身与生命相容，但小鼠加倍 我们的Meox 1等位基因纯合子和Meox 2敲除等位基因严重 在合作努力中受到影响。Meox 1和Meox 2 是两个相关的中胚层同源结构域转录因子， 共同建立中轴骨骼的复杂结构 有趣的是，纯合子Meox 1突变体女性不能泌乳，因为 怀孕后期乳腺发育的缺陷。 这是否 哺乳缺陷是由于基质或上皮缺陷， 正在研究乳腺移植。 以来 转基因插入导致了基因组DNA的缺失， 在Meox 1基因的3'端，骨骼表型可能是 和/或乳腺表型是由于对一个或多个 一个额外的基因位于Meox 1附近。 所以我们 开始尝试用Meox 1 cDNA拯救突变小鼠， 基于YAC的转基因策略。