Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain
Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain
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DOI：
10.1242/dev.123612
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发表时间：
2015-12-15
期刊：
影响因子：
4.6
通讯作者：
Petersen, Christian P.
中科院分区：
文献类型：
--
作者：
Hill, Eric M.;Petersen, Christian P.
决定最终器官大小的机制知之甚少。经历再生或正在进行的成年生长的动物可能需要持续和稳健的机制来实现和保持适当的大小。Planarians以其使用neoblast群体的多能成体干细胞进行全身再生的能力而闻名，可以通过控制细胞数量可逆地将身体大小扩大一个数量级。使用定量分析，我们发现，损伤后，涡虫完全恢复脑：身体比例增加脑细胞数量通过epimorphosis或减少脑细胞数量通过组织重塑（morphallaxis），视情况而定。我们确定了一条控制大脑大小设定点的途径，该途径涉及wnt 11 -6/wnt A/wnt 4a和背肌之间的反馈抑制，编码在相反脑极表达的保守拮抗信号因子。wnt 11 -6/wntA/wnt 4a通过经典Wnt信号传导经历反馈抑制，但可能独立于β-连环蛋白-1和APC以非经典途径调节脑大小。Wnt/Notum信号通过影响多能干细胞后代脑祖细胞的丰度来调节再生生长和组织重塑中分化脑细胞的数量，而不是调节细胞死亡。这些结果表明，最终器官大小的实现可能是通过实现平衡的位置信号输入，调节组织生产的速度。
Mechanisms determining final organ size are poorly understood. Animals undergoing regeneration or ongoing adult growth are likely to require sustained and robust mechanisms to achieve and maintain appropriate sizes. Planarians, well known for their ability to undergo whole-body regeneration using pluripotent adult stem cells of the neoblast population, can reversibly scale body size over an order of magnitude by controlling cell number. Using quantitative analysis, we showed that after injury planarians perfectly restored brain: body proportion by increasing brain cell number through epimorphosis or decreasing brain cell number through tissue remodeling (morphallaxis), as appropriate. We identified a pathway controlling a brain size set-point that involves feedback inhibition between wnt11-6/wntA/wnt4a and notum, encoding conserved antagonistic signaling factors expressed at opposite brain poles. wnt11-6/wntA/wnt4a undergoes feedback inhibition through canonical Wnt signaling but is likely to regulate brain size in a non-canonical pathway independently of beta-catenin-1 and APC. Wnt/Notum signaling tunes numbers of differentiated brain cells in regenerative growth and tissue remodeling by influencing the abundance of brain progenitors descended from pluripotent stem cells, as opposed to regulating cell death. These results suggest that the attainment of final organ size might be accomplished by achieving a balance of positional signaling inputs that regulate the rates of tissue production.