Extra-embryonic vasculature development is regulated by the transcription factor HAND1
Extra-embryonic vasculature development is regulated by the transcription factor HAND1
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DOI：
10.1242/dev.01091
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发表时间：
2004-05-01
期刊：
影响因子：
4.6
通讯作者：
Cserjesi, P
中科院分区：
文献类型：
--
作者：
Morikawa, Y;Cserjesi, P
碱性螺旋-环-螺旋（bHLH）转录因子HAND1（也称为eHAND）在心脏、四肢、神经嵴衍生物和胚胎外膜等多种组织的发育过程中表达。为了研究Hand1在发育过程中的作用，我们培育了一只Hand1基因敲除小鼠。hand1基因缺失的小鼠存活到9岁，在此期间，它们屈服于许多发育缺陷。hand1缺失胚胎的一个显著缺陷是由于卵黄囊血管系统的缺陷导致造血细胞在卵黄囊和羊膜之间积累。在Hand1-null卵黄囊中，血管发生，但血管细化被阻止。对胚胎外膜血管生成基因的分析表明，在hand1缺失的胚胎中，大多数血管生成基因的表达水平正常，但包括Vegf、Ang1和ephrin B2在内的一些基因成分以及Notch通路的基因成分上调。在缺乏Hand1的情况下，bHLH因子Hand2的表达也增强。尽管HAND1和HAND2具有许多相同的结构特征，而且HAND2是卵黄囊血管发育所必需的，但HAND2表达的增强不足以弥补HAND1的缺失。Hand1突变体卵黄囊血管缺损最显著的方面是平滑肌细胞的异常分布。在正常血管生成过程中，血管平滑肌前体细胞在分化前被招募到内皮周围组织，然而，在Hand1空卵黄囊中，平滑肌细胞没有被招募，而是以簇状分布在整个中胚层中。这些数据表明Hand1是卵黄囊血管生成和血管平滑肌募集所必需的。
The basic helix-loop-helix (bHLH) transcription factor HAND1 (also called eHAND) is expressed in numerous tissues during development including the heart, limbs, neural crest derivatives and extra-embryonic membranes. To investigate the role of Hand1 during development, we generated a Hand1 knockout mouse. Hand1-null mice survived to the nine somite stage at which time they succumbed to numerous developmental defects. One striking defect in Hand1-null embryos was the accumulation of hematopoietic cells between the yolk sac and the amnion because of defects in the yolk sac vasculature. In Hand1-null yolk sacs, vasculogenesis occurs but vascular refinement was arrested. Analysis of angiogenic genes in extra-embryonic membranes showed that most are expressed at normal levels in Hand1-null embryos but several, including Vegf, Ang1 and ephrin B2, and gene components of the Notch pathway are upregulated. In the absence of Hand1 the expression of the bHLH factor Hand2 is also enhanced. Although HAND1 and HAND2 share many structural features, and Hand2 is required for vasculature devellopment in yolk sacs, enhanced expression of Hand2 is insufficient to compensate for the loss of Hand1. The most striking aspect of the vascular defect in Hand1 mutant yolk sacs is the abnormal distribution of smooth muscle cells. During normal angiogenesis, vascular smooth muscle precursors are recruited to the peri-endothelial tissue before differentiation, however, in Hand1 null yolk sacs, smooth muscle cells are not recruited but differentiate in clusters distributed throughout the mesoderm. These data indicate that Hand1 is required for angiogenesis and vascular smooth muscle recruitment in the yolk sac.