Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract.
Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract.
复制标题
DOI：
10.1242/dev.022350
复制
发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Cleary ML
中科院分区：
文献类型：
--
作者：
Chang CP;Stankunas K;Shang C;Kao SC;Twu KY;Cleary ML
心血管系统进入体循环和肺循环是一个复杂的形态发生过程，如果失败，就会导致临床上重要的先天性缺陷。这个过程包括广泛的血管重塑和心脏流出道(OFT)的协调分割。我们证明了同源结构域转录因子Pbx1协调不同的转录途径来控制小鼠的大动脉模式和心脏OFT间隔。PBX1缺失的胚胎显示异常的大动脉，这是由于未能在咽尾部建立初始的颧弓动脉。Pbx1缺乏也会导致心脏OFT间隔失败。Pbx1基因缺失的胚胎失去了迁移前心脏神经脊细胞(NCC)中Pax3的瞬时爆发表达，该表达最终决定了心脏NCC对OFT发育的作用，但不调控NCC向心脏的迁移。我们发现Pbx1直接激活Pax3，导致其靶基因MSX2在NCC中受到抑制。复合MSX2/Pbx1缺失的胚胎显示出显著的心脏间隔挽救作用，表明Pbx1-Pax3-MSX2调节通路的中断部分地导致了Pbx1缺失小鼠的OFT缺陷。相反，MSX2/Pbx1缺失的复合胚胎的大动脉异常与Pbx1缺失的胚胎保持在相同的频谱内。因此，Pbx1在心血管发育的不同调控途径中起着至关重要的作用。
The patterning of the cardiovascular system into systemic and pulmonic circulations is a complex morphogenetic process, the failure of which results in clinically important congenital defects. This process involves extensive vascular remodeling and coordinated division of the cardiac outflow tract (OFT). We demonstrate that the homeodomain transcription factor Pbx1 orchestrates separate transcriptional pathways to control great-artery patterning and cardiac OFT septation in mice. Pbx1-null embryos display anomalous great arteries owing to a failure to establish the initial complement of branchial arch arteries in the caudal pharyngeal region. Pbx1 deficiency also results in the failure of cardiac OFT septation. Pbx1-null embryos lose a transient burst of Pax3 expression in premigratory cardiac neural crest cells (NCCs) that ultimately specifies cardiac NCC function for OFT development, but does not regulate NCC migration to the heart. We show that Pbx1 directly activates Pax3, leading to repression of its target gene Msx2 in NCCs. Compound Msx2/Pbx1-null embryos display significant rescue of cardiac septation, demonstrating that disruption of this Pbx1-Pax3-Msx2 regulatory pathway partially underlies the OFT defects in Pbx1-null mice. Conversely, the great-artery anomalies of compound Msx2/Pbx1-null embryos remain within the same spectrum as those of Pbx1-null embryos. Thus, Pbx1 makes a crucial contribution to distinct regulatory pathways in cardiovascular development.
登录
查看更多内容
影响因子：
2.7
作者：
Brown, CB;Wenning, JM;Epstein, JA
通讯作者：
Epstein, JA
影响因子：
10.8
作者：
Conway, SJ;Henderson, DJ;Copp, AJ
通讯作者：
Copp, AJ
影响因子：
64.5
作者：
Chang, CP;Neilson, JR;Crabtree, GR
通讯作者：
Crabtree, GR
影响因子：
4.6
作者：
Brendolan, A;Ferretti, E;Selleri, L
通讯作者：
Selleri, L
影响因子：
11.8
作者：
Kelly, RG;Brown, NA;Buckingham, ME
通讯作者：
Buckingham, ME