Martín-Castellanos Cristina, Edgar Bruce A
Fred Hutchinson Cancer Research Center, Division of Basic Sciences, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Development. 2002 Feb;129(4):1003-13. doi: 10.1242/dev.129.4.1003.
Cell proliferation and patterning must be coordinated for the development of properly proportioned organs. If the same molecules were to control both processes, such coordination would be ensured. Here we address this possibility in the Drosophila wing using the Dpp signaling pathway. Previous studies have shown that Dpp forms a gradient along the AP axis that patterns the wing, that Dpp receptors are autonomously required for wing cell proliferation, and that ectopic expression of either Dpp or an activated Dpp receptor, Tkv(Q253D), causes overgrowth. We extend these findings with a detailed analysis of the effects of Dpp signaling on wing cell growth and proliferation. Increasing Dpp signaling by expressing Tkv(Q253D) accelerated wing cell growth and cell cycle progression in a coordinate and cell-autonomous manner. Conversely, autonomously inhibiting Dpp signaling using a pathway specific inhibitor, Dad, or a mutation in tkv, slowed wing cell growth and division, also in a coordinate fashion. Stimulation of cell cycle progression by Tkv(Q253D) was blocked by the cell cycle inhibitor RBF, and required normal activity of the growth effector, PI3K. Among the known Dpp targets, vestigial was the only one tested that was required for Tkv(Q253D)-induced growth. The growth response to altering Dpp signaling varied regionally and temporally in the wing disc, indicating that other patterned factors modify the response.
细胞增殖和模式形成必须协调进行,才能发育出比例恰当的器官。如果相同的分子能控制这两个过程,那么这种协调就能得到保证。在这里,我们利用果蝇翅膀中的Dpp信号通路来探讨这种可能性。先前的研究表明,Dpp沿前后轴形成梯度,从而决定翅膀的模式;Dpp受体对于翅膀细胞增殖是自主必需的;异位表达Dpp或活化的Dpp受体Tkv(Q253D)会导致过度生长。我们通过详细分析Dpp信号对翅膀细胞生长和增殖的影响,扩展了这些发现。通过表达Tkv(Q253D)增加Dpp信号,以协调且细胞自主的方式加速了翅膀细胞生长和细胞周期进程。相反,使用通路特异性抑制剂Dad或tkv突变自主抑制Dpp信号,也以协调的方式减缓了翅膀细胞生长和分裂。Tkv(Q253D)对细胞周期进程的刺激被细胞周期抑制剂RBF阻断,并且需要生长效应器PI3K的正常活性。在已知的Dpp靶标中,vestigial是唯一被测试的、Tkv(Q253D)诱导生长所必需的靶标。在翅芽中,对改变Dpp信号的生长反应在区域和时间上有所不同,这表明其他模式因子会改变这种反应。