Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation
Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation
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DOI：
10.1046/j.1365-2443.2000.00339.x
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发表时间：
2000-06-01
期刊：
影响因子：
2.1
通讯作者：
Noda, T
中科院分区：
文献类型：
--
作者：
Akazawa, H;Komuro, I;Noda, T
背景：NK同源异型盒基因在细胞类型分化和器官形成中起重要作用。小鼠Bapx 1是NK同源异型盒基因家族的成员之一，在软骨内成骨的所有软骨组织和胚胎发育过程中的肠系膜中都有表达，提示Bapx 1可能是调控这些器官发育的关键转录因子。Bapx 1（-/-）小鼠表现出致命的骨骼发育不良，脊柱和一些颅面骨发育异常，伴有无脾和胃十二指肠畸形。我们发现，在Bapx 1（-/-）胚胎中，形成脊柱的硬结细胞的增殖活性显著降低。突变体的硬节细胞似乎正常迁移和凝聚，但随后分化为成熟的椎体和椎间盘受到影响。椎体中的硬节细胞不能分化为肥大的软骨细胞，如未检测到的Col 10a 1和骨桥蛋白的表达所示，椎间盘中的硬节细胞不能表达典型的细胞外基质蛋白Col 2a 1、Col 9a 2和聚集蛋白聚糖。此外，我们研究了Bapx 1缺失对一些转录因子表达的影响，这些转录因子被鉴定为在发育中的硬骨节中表达，并且是脊柱正常发育所需的。其中，我们发现MFH-1的表达，在Bapx 1（-/-）小鼠的腹内侧巩膜节细胞中，据报道调节巩膜节细胞增殖和分化的间充质叉头-1（mesenchymeforkhead-1）显著减少。我们的分析提供了Bapx 1对脊柱腹内侧结构和某些颅面骨的正常发育不可缺少的证据，脾发生和胃十二指肠管形态发生。
Background: NK homeobox genes have been shown to play important roles in cell-type specification and organogenesis. Murine Bapx1, a member of NK homeobox gene family, is expressed in all the cartilageous tissues that undergo endochondral bone formation, and in gut mesentery during embryogenesis, suggesting that Bapx1 may be a key transcription factor ragulating the development of these organs.Results: We generated Bapx1-deficient mice by gene targeting. Bapx1(-/-) mice exhibited lethal skeletal dysplasia, with abnormal development of the vertebral column and some craniofacial bones, accompanied with asplenia and gastroduodenal malformation. We showed that the proliferative activity of the sclerotome cells, forming the vertebral column, was significantly reduced in Bapx1(-/-) embryos. The sclerotome cells of the mutants appeared to migrate and condense normally, but subsequent differentiation into the mature vertebral bodies and intervertebral discs were affected. The sclerotome cells in the vertebral bodies failed to differentiate into hypertrophic chondrocytes, as revealed by the undetected expression of Col10a1 and Osteopontin, and the sclerotome cells in the intervertebral discs failed to express the typical extracellular matrix proteins Col2a1, Col9a2 and aggrecan. Furthermore, we investigated the effect of loss of Bapx1 on the expression of some transcription factors, identified to be expressed in the developing sclerotome and be required for normal development of the vertebral column. Among them, we found that the expression of MFH-1 (mesenchyme forkhead-1), which was reported to regulate the proliferation and differentiation of sclerotome cells, was significantly reduced in ventromedial sclerotome cells in Bapx1(-/-) mice.Conclusion: Our analysis provided evidence that Bapx1 was indispensable for normal development of ventromedial structure of vertebral column and some of craniofacial bones, splenogenesis and morphogenesis of gastroduodenal tract.