Manley N R, Capecchi M R
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City 84112, USA.
Development. 1995 Jul;121(7):1989-2003. doi: 10.1242/dev.121.7.1989.
Targeted disruption of Hoxa-3 results in a number of regionally restricted defects in tissues and structures derived from or patterned by mesenchymal neural crest. However, analysis of mutant embryos with injections of a carbocyanine dye or with molecular markers that label these cells indicates that neither the amount nor the migration patterns of this neural crest population are grossly affected. Therefore, it appears that the loss of Hoxa-3 affects the intrinsic capacity of this neural crest cell population to differentiate and/or to induce proper differentiation of the surrounding pharyngeal arch and pouch tissues. Hoxa-3 mutant mice are athymic and show thyroid hypoplasia. Thymus development is first evident as an expansion of mesenchymal neural crest in the posterior part of the 3rd pharyngeal pouch. Prior to this expansion, a marked reduction in pax-1 expression is observed in these cells in the mutant embryos. As pax-1 mutant mice also show thymic hypoplasia, these results suggest that Hoxa-3 may be required to maintain pax-1 expression in these cells and that the reduction of pax-1 expression is part of the athymic teleology in Hoxa-3 mutant mice. The thyroid gland is formed from the fusion of two structures of separate embryonic origin, the thyroid diverticulum, which is formed from endodermal epithelium in the floor of the pharynx, and the ultimobranchial body, formed from mesenchymal neural crest in the 4th pharyngeal pouch. Both of these sites express Hoxa-3 and are defective in mutant mice. Often a vesicle is observed in mutant mice that is exclusively composed of calcitonin-producing cells, suggesting the persistence of an ultimobranchial body. Both aspects of the thyroid phenotype show variable expressivity among mutant animals, even on the two sides of the same mutant animal. This variability suggests the presence of a compensating gene or genes, whose utilization is stochastic. A reasonable candidate for providing this compensatory function is the paralogous gene Hoxb-3.
Hoxa - 3基因的靶向破坏会导致源自间充质神经嵴或由其形成模式的组织和结构出现一些区域特异性缺陷。然而，对注射了羰花青染料的突变胚胎或用标记这些细胞的分子标记物进行分析表明，这群神经嵴细胞的数量和迁移模式均未受到严重影响。因此，Hoxa - 3的缺失似乎影响了这群神经嵴细胞分化和/或诱导周围咽弓和咽囊组织正常分化的内在能力。Hoxa - 3突变小鼠无胸腺且甲状腺发育不全。胸腺发育最初表现为第3咽囊后部间充质神经嵴的扩展。在此扩展之前，在突变胚胎的这些细胞中观察到pax - 1表达显著降低。由于pax - 1突变小鼠也表现出胸腺发育不全，这些结果表明Hoxa - 3可能是维持这些细胞中pax - 1表达所必需的，并且pax - 1表达的降低是Hoxa - 3突变小鼠无胸腺机制的一部分。甲状腺由两个起源于不同胚胎结构融合而成，甲状腺憩室由咽底部的内胚层上皮形成，最后鳃体由第4咽囊的间充质神经嵴形成。这两个部位均表达Hoxa - 3且在突变小鼠中存在缺陷。在突变小鼠中经常观察到一个仅由产生降钙素的细胞组成的囊泡，提示最后鳃体持续存在。甲状腺表型的这两个方面在突变动物中表现出可变的表达，甚至在同一突变动物的两侧也是如此。这种变异性表明存在一个或多个补偿基因，其利用是随机的。提供这种补偿功能的一个合理候选基因是同源基因Hoxb - 3。
