MESODERMAL HOMEODOMAIN PROTEIN DURING VERTEBRA DEVELOPMENT

椎骨发育过程中的中胚层同源域蛋白

• 批准号: 5203145
• 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/5203145
• 关键词: DNA binding protein; developmental neurobiology; gene deletion mutation; gene expression; gene rearrangement; genetically modified animals; laboratory mouse; mesoderm; phenotype; transposon /insertion element; vertebrae

The structures that encase the central nervous system - the vertebra and the skull - develop from somitic mesoderm and from the neural crest. The molecular mechanisms that underlie this developmental process have not been studied widely. We have obtained a murine transgenic insertional mutation with a recessive phenotype characterized by hemivertebrae, vertebral fusions, and fusions between skull and atlas. We now have determined that the insertion occurred in the first intron of the mesodermal homeodomain gene mox1. This gene is expressed in mesoderm as early as the primitive streak stage and later in presomitic mesoderm, differentiating somites, and mesenchyme of the heart cushion, truncus arteriosus and craniofacial neural crest. The insertion was accompanied by a deletion extending beyond the 3' end of the gene. However, genomic P1 clones that contain the entire mox1 gene plus additional 3' sequences have allowed us to span the deletion. Since there is no evidence for additional gross rearrangements or deletions in the chromosomal area surrounding the insertion, it is likely that the phenotype is due solely to the disruption of the mox1 gene. The phenotype is consistent with a role of mox1 in the formation of preskeletal condensations and indicates that related homeodomain proteins such as mox2 with partly overlapping expression patterns are not able to compensate for the loss of mox1. Future studies will show whether the role of mox1 is primarily in regulating growth rates of mesenchymal cells, thus specifying the time points and locations of condensations and the formation of ossification centers, or has additional function in specifying the identity of structures of the axial skeleton. The results will have impact on understanding skeletal and skull malformations in mice and humans as well.

包围中枢神经系统的结构 - 椎骨和 头骨 - 由体节中胚层和神经嵴发育而来。这 这一发育过程的分子机制尚未 被广泛研究。 我们已经获得了小鼠转基因插入 具有以半椎骨为特征的隐性表型的突变， 椎骨融合，以及颅骨和寰椎之间的融合。我们现在有 确定插入发生在第一个内含子中 中胚层同源域基因 mox1。 该基因在中胚层中表达为 早在原条阶段，晚在前体中胚层， 区分心垫、干的体节和间质 动脉和颅面神经嵴。 插入伴随 通过延伸超出基因 3' 端的缺失。 然而，基因组 包含整个 mox1 基因以及额外 3' 序列的 P1 克隆 允许我们跨越删除。由于没有证据表明 染色体区域额外的总体重排或缺失 围绕插入，很可能表型仅归因于 mox1 基因的破坏。 表型符合 mox1 在前骨骼凝聚形成中的作用并表明 相关同源结构域蛋白，例如 mox2，部分重叠 表达模式无法补偿 mox1 的损失。 未来的研究将表明 mox1 的作用是否主要在于 调节间充质细胞的生长速率，从而指定时间 凝结和骨化形成的点和位置 中心，或具有指定身份的附加功能 中轴骨架的结构。 结果将影响 了解小鼠和人类的骨骼和颅骨畸形 出色地。