MESODERMAL HOMEODOMAIN PROTEIN DURING VERTEBRAL DEVELOPMENT

器官的形状和大小由 其单元格的位置、数量和大小依次取决于单元格 增殖、细胞迁移和细胞死亡。有趣的一点是 病例是在不同轴向水平上进行的体细胞发生 刻板印象的路径，但导致不同大小的结构和 形状。我们已经分析了一系列带有隐性基因的转基因小鼠 以区域特异性为特征的插入突变 中轴线骨骼的改变，特别是在 颅颈关节。这些小鼠也有一个严重的缺陷 哺乳。有趣的是，这些表型中的每一种都有自己的 蛋白质突变小鼠的相应基因 已知或被认为与细胞的调节有关 扩散。我们发现插入创建了一个 编码Meox1基因的功能缺失突变 同源结构域转录因子。这一因素与 同源结构域蛋白Meox2，也被称为Gax，其 过度表达会导致多种培养细胞的生长停滞。 为了测试Meox1和Meox2之间的遗传交互作用，我们 在合作努力下，分析了Meox1和Meox2 在Meox1和Meox2突变小鼠中表达并发现 一个基因的突变不会对 他者的表达。而小鼠在这两种情况下都是纯合的 单一突变至少能活到断奶，Meox1/Meox2加倍 突变体是死产的，显示出基本的轴向骨骼，融合 背根神经节，不均匀分布的运动轴突，并且缺乏肋骨。 这些变化是由于体节的畸形造成的 大小、形状和间距都不规则，缺乏细胞 通常发生在尾部的凝结 硬化症。因此，Meox1和Meox2协同行动，以实现 核盘菌的正常发育，但它们如何发挥其作用 功能目前尚不明确。特别是，目前还不清楚 Meox1或Meox2在体内减少细胞增殖以及如何丢失 这些蛋白质的功能会导致特定基因的缺失 结构。我们的研究的最终目的是阐明 潜在的分子和细胞生物学机制并测试 具有相似病理的人类是否可能在 同源基因。

The shape and size of organs is controlled by the position, number, and size of its cells which in turn depend on cell proliferation, cell migration, and cell death. An interesting point in case is somitogenesis which in different axial levels proceeds along stereotypic pathways but leads to structures of distinct size and shape. We have analyzed a line of transgenic mice with a recessive insertional mutation that is characterized by region-specific alterations in the axial skeleton, particularly in the area of the cranio-cervical joint. These mice also have a severe deficiency in lactation. Intriguingly, each of these phenotypes has its corresponding counterpart in mice with mutations in proteins known or thought to be involved in the regulation of cell proliferation. We found that the insertion has created a loss-of-function mutation in the gene encoding the Meox1 homeodomain transcription factor. This factor is related to the homeodomain protein Meox2, also known as Gax, whose overexpression leads to growth arrest of a variety of cultured cells. To test for genetic interactions between Meox1 and Meox2, we have, in collaborative efforts, analyzed Meox1 and Meox2 expression in Meox1 and Meox2 mutant mice and found that mutations in one gene do not lead to striking effects on the expression of the other. While mice homozygous for either of the single mutations live at least to weaning, Meox1/Meox2 double mutants are stillborn, display a rudimentary axial skeleton, fused dorsal root ganglia, unevenly spaced motor axons, and lack ribs. These alterations result from malformations in the somites which are irregularly sized, shaped, and spaced and lack the cellular condensations that normally occur in the caudal parts of the sclerotome. Thus, Meox1 and Meox2 act in concert to bring about the normal development of the sclerotome, but how they exert their function is not clear at present. In particular, it is unknown whether Meox1 or Meox2 reduce cell proliferation in vivo and how a loss of function in these proteins would lead to deletions of particular structures. Our studies have the final goal to elucidate the underlying molecular and cell biological mechanisms and to test whether humans with similar pathology may have mutations in the homologous genes.