Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods
Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods
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DOI：
10.1006/dbio.1998.9176
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发表时间：
1999-04-01
影响因子：
2.7
通讯作者：
Mark, M
中科院分区：
文献类型：
--
作者：
Dupé, V;Ghyselinck, NB;Mark, M
我们先前报道了缺乏RAR γ基因和RAR β基因的一个或两个等位基因的小鼠（即，RAR β（+/-）/RAR γ（-/-）和RAR β（-/-）/RAR γ（-/-）突变体）显示出严重的和完全渗透的趾间蹼（软组织并指），这是由胎儿趾间间充质的持续性引起的（Ghyselinck等人，1997，Int. J. Dev. 41，425-447）。在本研究中，这些复合突变体被用来调查涉及的细胞和分子机制，视黄酸（RA）依赖性的趾间坏死区（INZ）的形成。突变的INZ显示凋亡细胞的数量显著减少，伴随着细胞增殖的增加。这种显著的减少并没有被巨噬细胞数量的减少所抵消，这表明通常吸引这些细胞进入INZ的趋化性线索没有受到影响。已知参与INZ建立、自足模式化和/或细胞凋亡起始的许多基因的表达也不受影响。这些基因包括BMP-2、BMP-4、Msx-1、Msx-2、Hox复合物的5'成员、Bcl 2、Bar和p53。相比之下，突变体INZ在从RAR γ无效遗传背景中去除RAR β基因的一个或两个等位基因后，显示出组织转氨酶（tTG）启动子活性和基质分解素-3表达的特异性、分级、下调。由于视黄酸反应元件存在于tTG和基质分解素-3基因的启动子区域中，我们提出RA可能通过直接调节tTG表达来增加INZ中的细胞死亡量，并且它还通过上调INZ中基质分解素-3表达来促进伴随细胞死亡的组织重塑过程。大约10%的RAR β（-/-）/RAR γ（-/-）突变体在后足上显示额外的轴前趾，这也是BMP-7无效表型的特征（达德利ct at，1995，Genes Dev. 9，2795-2807; Luo等人，1995，Genes Dev. 9，2808-2820）。BMP-7在这些RAR双无效突变体的autopods的早期阶段被全局下调，在数字射线出现之前。因此，RA可能通过控制BMP-7的表达而对前后足模式产生影响。(C)北京：科学出版社.
We previously reported that mice lacking the RAR gamma gene and one or both alleles of the RAR beta gene (i.e., RAR beta(+/-)/RAR gamma(-/-) and RAR beta(-/-)/RAR gamma(-/-) mutants) display a severe and fully penetrant interdigital webbing (soft tissue syndactyly), caused by the persistence of the fetal interdigital mesenchyme (Ghyselinck ct al., 1997, Int. J. Dev. Biol. 41, 425-447). In the present study, these compound mutants were used to investigate the cellular and molecular mechanisms involved ill retinoic acid (RA)-dependent formation of the interdigital necrotic zones (INZs). The mutant INZs show a marked decrease in the number of apoptotic cells accompanied by an increase of cell proliferation. This marked decrease was not paralleled by a reduction of the number of macrophages, indicating that the chemotactic cues which normally attract these cells into the INZs were not affected. The expression of a number of genes known to be involved in the establishment of the INZs, the patterning of the autopod, and/or the initiation of apoptosis was also unaffected. These genes included BMP-2, BMP-4, Msx-1, Msx-2, 5' members of Hox complexes, Bcl2, Bar, and p53. In contrast the mutant INZs displayed a specific, graded, down-regulation of tissue transglutaminase (tTG) promoter activity and of stromelysin-3 expression upon the removal of one or both alleles of the RAR beta gene from the RAR gamma null genetic background. As retinoic acid response elements are present in the promoter regions of both tTG and stromelysin-3 genes,we propose that RA might increase the amount of cell death in the INZs through a direct modulation of tTG expression and that it also contributes to the process of tissue remodeling, which accompanies cell death, through an up-regulation of stromelysin-3 expression ill the INZs. Approximately 10% of the RAR beta(-/-) /RAR gamma(-/-) mutants displayed a supernumerary preaxial digit on hindfeet, which is also a feature of the BMP-7 null phenotype (Dudley ct at, 1995, Genes Dev. 9, 2795-2807; Luo ct at, 1995, Genes Dev. 9, 2808-2820). BMP-7 was globally down-regulated at an early stage in the autopods of these RAR double null mutants, prior to the appearance of the digital rays. Therefore, RA may exert some of its effects on anteroposterior autopod patterning through controlling BMP-7 expression. (C) 1999 Academic Press.