Frasch M, Chen X, Lufkin T
Brookdale Center for Molecular Biology, Mount Sinai Medical Center, New York, NY 10029-6574, USA.
Development. 1995 Apr;121(4):957-74. doi: 10.1242/dev.121.4.957.
The HOM-C/Hox complexes are an evolutionary related family of genes that have been shown to direct region-specific development of the animal body plan. We examined in transgenic mice the DNA regulatory elements that determine the temporal and spatially restricted expression of two of the earliest and most anteriorly expressed murine genes, Hoxa-1 and Hoxa-2, which are homologues of the labial and proboscipedia genes of Drosophila. In both mouse and Drosophila, these genes have been shown to play a critical role in head development. We identified three independent enhancers which direct distinct portions of the Hoxa-1 and Hoxa-2 expression domains during early murine embryogenesis. Two enhancers mediate hindbrain-specific expression, being active in either rhombomere 2, the most anterior rhombomere expressing Hoxa-2, or in rhombomere 4, a region where Hoxa-1 and Hoxa-2 have been shown to exert critical developmental roles. The third enhancer is essential for the most extensive expression domain of Hoxa-1 and contains a retinoic acid response element. Point mutations within the retinoic acid response element abolish expression in neuroepithelium caudal to rhombomere 4, supporting a natural role for endogenous retinoids in patterning of the hindbrain and spinal cord. Analysis of the murine Hoxa-2 rhombomere 2-specific enhancer in Drosophila embryos revealed a distinct expression domain within the arthropod head segments, which parallels the expression domain of the Hoxa-2 homologue proboscipedia. These results suggest an evolutionary conservation between HOM-C/Hox family members, which includes a conservation of certain DNA regulatory elements and possible regulatory cascades.
HOM-C/Hox复合体是一个与进化相关的基因家族，已被证明可指导动物身体结构的区域特异性发育。我们在转基因小鼠中研究了DNA调控元件，这些元件决定了最早且最靠前表达的两个小鼠基因Hoxa-1和Hoxa-2的时空限制性表达，它们是果蝇唇基因和触须基因的同源物。在小鼠和果蝇中，这些基因已被证明在头部发育中起关键作用。我们鉴定出三个独立的增强子，它们在小鼠早期胚胎发育过程中指导Hoxa-1和Hoxa-2表达域的不同部分。两个增强子介导后脑特异性表达，在表达Hoxa-2的最靠前的菱脑节2或在Hoxa-1和Hoxa-2已被证明发挥关键发育作用的菱脑节4区域中具有活性。第三个增强子对于Hoxa-1最广泛的表达域至关重要，并且包含一个视黄酸反应元件。视黄酸反应元件内的点突变消除了菱脑节4尾侧神经上皮中的表达，支持内源性类视黄醇在菱脑和脊髓模式形成中的天然作用。在果蝇胚胎中对小鼠Hoxa-2菱脑节2特异性增强子的分析揭示了节肢动物头部节段内一个独特的表达域，它与Hoxa-2同源物触须基因的表达域平行。这些结果表明HOM-C/Hox家族成员之间存在进化保守性，包括某些DNA调控元件和可能的调控级联的保守性。
