Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4
Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4
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DOI：
10.1006/dbio.1997.8664
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发表时间：
1997-08-15
影响因子：
2.7
通讯作者：
Hogan, BLM
中科院分区：
文献类型：
--
作者：
Dunn, NR;Winnier, GE;Hogan, BLM
骨形态发生蛋白 4 (Bmp4) 是果蝇 decapentaplegic (dpp) 的脊椎动物同源物，编码一种在胚胎发生过程中具有多种功能的信号蛋白。大多数 Bmp4(tm1blh) 无效等位基因纯合的小鼠胚胎在原肠胚形成时死亡，几乎没有或没有中胚层。将两个独立衍生的 Bmp4(tm1) 突变回交到 C57BL/6 遗传背景上。在杂合子中观察到几种独立表达的、不完全渗透的异常，包括囊性肾、颅面畸形、小眼畸形和右后肢轴前多指畸形。此外，断奶时杂合子的代表性始终不足。这些结果表明 Bmp4 基因剂量对于多种器官的正常发育和新生儿的生存能力至关重要。确定了增强多指表型外显率和表达能力的两个突变：Gli3(XtJ)，一种涉及编码与 Drosophila cubitus Interruptus 相关的锌指蛋白的基因的缺失突变；以及 Alx4(mt1rwm)，一种编码与 Drosophila aristaless 相关的配对类同源蛋白的基因的靶向 mil 突变。所有双 Bmp4(tm1)； Gli3(XtJ)杂合子的前肢和后肢都有广泛的前部异常，而所有双Bmp4(tm1)； Alx4(tm1) 杂合子仅在后肢上显示异位前指。这些遗传相互作用提出了脊椎动物肢体发育过程中前指模式的多基因控制模型。 (C) 1997 年学术出版社。
Bone morphogenetic protein 4 (Bmp4), a vertebrate homolog of Drosophila decapentaplegic (dpp), encodes a signaling protein with multiple functions during embryogenesis. Most mouse embryos homozygous for the Bmp4(tm1blh) null allele die around the time of gastrulation, with little or no mesoderm. Two independently derived Bmp4(tm1) mutations were backcrossed onto the C57BL/6 genetic background. Several independently expressed, incompletely penetrant abnormalities were observed in heterozygotes, including cystic kidney, craniofacial malformations, microphthalmia, and preaxial polydactyly of the right hindlimb. In addition, heterozygotes were consistently underrepresented at weaning. These results indicate that Bmp4 gene dosage is essential for the normal development of a variety of organs and for neonatal viability. Two mutations that enhance the penetrance and expressivity of the polydactylous phenotype were identified: Gli3(XtJ) a deletion mutation involving a gene encoding a zinc-finger protein related to Drosophila cubitus interruptus, and Alx4(mt1rwm), a targeted mil mutation in a gene encoding a paired class homeoprotein related to Drosophila aristaless. All double Bmp4(tm1); Gli3(XtJ) heterozygotes have extensive anterior di,ait abnormalities of both fore-and hindlimbs, while all double Bmp4(tm1); Alx4(tm1) heterozygotes display ectopic anterior digits only on the hindlimbs. These genetic interactions suggest a model for the multigenic control of anterior digit patterning during vertebrate limb development. (C) 1997 Academic Press.