Cunningham Thomas J, Kumar Sandeep, Yamaguchi Terry P, Duester Gregg
Development, Aging, and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, California.
Cancer and Developmental Biology Laboratory, NCI-Frederick, National Institutes of Health, Frederick, Maryland.
Dev Dyn. 2015 Jun;244(6):797-807. doi: 10.1002/dvdy.24275. Epub 2015 Apr 23.
Vertebrate body axis extension occurs in a head-to-tail direction from a caudal progenitor zone that responds to interacting signals. Wnt/β-catenin signaling is critical for generation of paraxial mesoderm, somite formation, and maintenance of the axial stem cell pool. Body axis extension requires Wnt8a in lower vertebrates, but in mammals Wnt3a is required, although the anterior trunk develops in the absence of Wnt3a.
We examined mouse Wnt8a(-/-) and Wnt3a(-/-) single and double mutants to explore whether mammalian Wnt8a contributes to body axis extension and to determine whether a posterior growth function for Wnt8a is conserved throughout the vertebrate lineage. We find that caudal Wnt8a is expressed only during early somite stages and is required for normal development of the anterior trunk in the absence of Wnt3a. During this time, we show that Wnt8a and Wnt3a cooperate to maintain Fgf8 expression and prevent premature Sox2 up-regulation in the axial stem cell niche, critical for posterior growth. Similar to Fgf8, Wnt8a requires retinoic acid (RA) signaling to restrict its caudal expression boundary and possesses an upstream RA response element that binds RA receptors.
These findings provide new insight into interaction of caudal Wnt-FGF-RA signals required for body axis extension.
脊椎动物的体轴延伸是从一个对相互作用信号作出反应的尾侧祖细胞区开始，以头到尾的方向进行的。Wnt/β-连环蛋白信号传导对于轴旁中胚层的产生、体节形成以及轴向干细胞池的维持至关重要。在低等脊椎动物中，体轴延伸需要Wnt8a，但在哺乳动物中则需要Wnt3a，尽管在前体轴在没有Wnt3a的情况下也能发育。
我们研究了小鼠Wnt8a(-/-)和Wnt3a(-/-)单突变体和双突变体，以探讨哺乳动物Wnt8a是否有助于体轴延伸，并确定Wnt8a的后生长功能在整个脊椎动物谱系中是否保守。我们发现尾侧Wnt8a仅在早期体节阶段表达，并且在没有Wnt3a的情况下对于前体轴的正常发育是必需的。在此期间，我们表明Wnt8a和Wnt3a协同维持Fgf8表达，并防止轴向干细胞龛中Sox2过早上调，这对后生长至关重要。与Fgf8类似，Wnt8a需要视黄酸（RA）信号传导来限制其尾侧表达边界，并拥有一个与RA受体结合的上游RA反应元件。
这些发现为体轴延伸所需的尾侧Wnt-FGF-RA信号相互作用提供了新的见解。
