Requirement of the mouse I-mfa gene for placental development and skeletal patterning
Requirement of the mouse I-mfa gene for placental development and skeletal patterning
复制标题
DOI：
10.1093/emboj/17.21.6276
复制
发表时间：
1998-11-02
期刊：
影响因子：
11.4
通讯作者：
Groudine, M
中科院分区：
文献类型：
--
作者：
Kraut, N;Snider, L;Groudine, M
bHLH-阻遏蛋白I-mfa与MyoD家族成员结合，抑制其活性，并阻断其核输入和与DNA的结合。原位杂交分析表明，小鼠I-mfa在软骨形成发生之前在胚胎外谱系、在硬骨节中以及随后在轴骨和无骨关节骨骼的间充质前体中高度表达。在C57 B1/6背景中靶向缺失I-mfa导致E10.5左右的胚胎死亡，与胎盘缺陷和滋养层巨细胞数量显著减少相关。在大鼠滋养层（Rcho-1）干细胞中过表达I-mfa诱导分化为滋养层巨细胞。I-mfa与滋养层巨细胞形成的负调节因子bHLH蛋白Mash 2相互作用，并抑制其在细胞培养中的转录活性。相反，I-mfa不干扰巨细胞分化的正调节因子bHLH蛋白Hand 1的活性。有趣的是，在129/Sv背景下的I-mfa-null胚胎没有胎盘缺陷，通常存活至成年，并表现出延迟的尾神经管闭合和骨骼图案缺陷，包括肋骨、椎体融合和棘突异常形成。我们的研究结果表明，I-mfa在滋养层和软骨分化中起着重要的作用，负调控谱系限制的bHLH蛋白的一个子集。
The bHLH-repressor protein I-mfa binds to MyoD family members, inhibits their activity, and blocks their nuclear import and binding to DNA, In situ hybridization analysis demonstrated that mouse I-mfa was highly expressed in extraembryonic lineages, in the sclerotome, and subsequently within mesenchymal precursors of the axial and appendicular skeleton, before chondrogenesis occurs. Targeted deletion of I-mfa in a C57Bl/6 background resulted in embryonic lethality around E10.5, associated with a placental defect and a markedly reduced number of trophoblast giant cells, Overexpression of I-mfa in rat trophoblast (Rcho-1) stem cells induced differentiation into trophoblast giant cells. I-mfa interacted with the bHLH protein Mash2, a negative regulator of trophoblast giant cell formation, and inhibited its transcriptional activity in cell culture, In contrast, I-mfa did not interfere with the activity of the bHLH protein Hand1, a positive regulator of giant cell differentiation. Interestingly I-mfa-null embryos on a 129/Sv background had no placental defect, generally survived to adulthood, and exhibited delayed caudal neural tube closure and skeletal patterning defects that included fusions of ribs, vertebral bodies and abnormal formation of spinous processes. Our results indicate that I-mfa plays an important role in trophoblast and chondrogenic differentiation by negatively regulating a subset of lineage-restricted bHLH proteins.