Abstract:
Left-right patterning is among the least well understood of the three axes defining the body plan, and yet it is no less important, with left-right patterning defects causing structural birth defects with high morbidity and mortality, such as complex congenital heart disease, biliary atresia, or intestinal malrotation. The cell signaling pathways governing left-right asymmetry are highly conserved and involve multiple components of the TGF-β superfamily of cell signaling molecules. Central to left-right patterning is the differential activation of Nodal on the left, and BMP signaling on the right. In addition, a plethora of other cell signaling pathways including Shh, FGF, and Notch also contribute to the regulation of left-right patterning. In vertebrate embryos such as the mouse, frog, or zebrafish, the specification of left-right identity requires the left-right organizer (LRO) containing cells with motile and primary cilia that mediate the left-sided propagation of Nodal signaling, followed by left-sided activation of Lefty and then Pitx2, a transcription factor that specifies visceral organ asymmetry. While this overall scheme is well conserved, there are striking species differences, including the finding that motile cilia do not play a role in left-right patterning in some vertebrates. Surprisingly, the direction of heart looping, one of the first signs of organ left-right asymmetry, was recently shown to be specified by intrinsic cell chirality, not Nodal signaling, possibly a reflection of the early origin of Nodal signaling in radially symmetric organisms. How this intrinsic chirality interacts with downstream molecular pathways regulating visceral organ asymmetry will need to be further investigated to elucidate how disturbance in left-right patterning may contribute to complex CHD.
摘要:
左右图案是定义身体平面的三个轴最不容易理解的。然而这也同样重要,左右模式缺陷导致结构性出生缺陷,发病率和死亡率高,比如复杂的先天性心脏病,胆道闭锁,或者肠旋转不良。控制左右不对称性的细胞信号传导途径是高度保守的,并且涉及细胞信号传导分子的TGF-β超家族的多个组分。中央到左右的图案是左侧节点的差分激活,右边是BMP信号。此外,大量的其他细胞信号通路,包括Shh,FGF,和缺口也有助于左右图案的调节。在脊椎动物胚胎如小鼠中,青蛙,或者斑马鱼,左右身份的规范要求左右组织者(LRO)包含具有能动和初级纤毛的细胞,这些细胞介导了Nodal信号的左侧传播,然后是Lefty的左侧激活,然后是Pitx2,这是一种指定内脏器官不对称性的转录因子。虽然这个整体方案很保守,有显著的物种差异,包括发现活动纤毛在某些脊椎动物的左右模式中不起作用。令人惊讶的是,心脏循环的方向,器官左右不对称的第一个迹象之一,最近被证明是由内在细胞手性所指定的,不是节点信令,可能反映了径向对称生物中节点信号的早期起源。这种内在的手性如何与调节内脏器官不对称性的下游分子途径相互作用将需要进一步研究,以阐明左右模式的干扰如何导致复杂的CHD。