Signal scaling during limb regeneration of different sized animals

不同体型动物肢体再生过程中的信号缩放

• 批准号: 441649267
• 负责人: Professor Dr. Benjamin M. Friedrich
• 金额: --
• 依托单位: IMBA - Institute of Molecular Biotechnology GmbH
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/441649267?language=en
• 关键词: Signal; scaling; during; limb; regeneration

The ability of the axolotl to regenerate a complete limb at all post-embryonic stages, ranging from the 2-cm larvae to the 20-cm adult, provides a remarkable opportunity to understand how morphogen systems scale with system/tissue size. Limb amputation results in the formation of a blastema, which contains mesenchymal progenitors that express the same developmental factors as those found in the embryonic limb bud of the axolotl and other vertebrates. Importantly, the size of the regenerating axolotl blastema scales with body size, strongly suggesting that the range of action of developmental factors also scale with body size. The central aim of this proposal is to combine quantitative imaging with quantitative profiling of molecular signalling factors to enable mathematical modelling, with the ultimate goal to understand whether spatial domains of signaling scale in the axolotl limb blastema of different sized animals. We will experimentally test and perform mathematical modelling of two alternative hypotheses for how limb signalling can adapt to different blastema sizes. Hypothesis 1: Signalling gradients are established by effective diffusion. There is size-dependent modulation of effective diffusion coefficients, degradation rates, or sensitivity to signaling in small versus large blastemas. Hypothesis 2: Signaling fields are established by propagating waves, where blastema cells serve as relay units for signal propagation. To discriminate between hypotheses 1 and 2, and elucidate their mechanistic basis, we will: 1) Measure effective diffusion coefficients and sensitivity to signal perception of signaling factors in small and large blastemas 2) Create reporters and assay potential propagating waves of signaling that could drive signal propagation 3) Generate mathematical models of morphogen gradient scaling, derive testable predictions, and design discriminatory experiments 4) Finally, we will address which molecules regulate the size of expression and activity domains of the limb morphogens by implementing TomoSeq combined with functional assays.

蝾螈在所有胚胎后阶段再生一个完整肢体的能力，从2厘米的幼虫到20厘米的成年人，提供了一个显着的机会来了解形态系统如何与系统/组织大小的规模。断肢导致胚基的形成，其中含有表达与蝾螈和其他脊椎动物的胚胎肢芽中发现的相同发育因子的间充质祖细胞。重要的是，再生蝾螈芽基的大小与身体大小的规模，强烈表明，发展因素的行动范围也与身体大小的规模。 该建议的中心目的是将联合收割机定量成像与分子信号因子的定量分析相结合，以实现数学建模，最终目标是了解不同大小动物的蝾螈肢体芽基中信号尺度的空间域。我们将实验测试和执行数学建模的两个替代假设，肢体信号可以适应不同的芽基大小。 假设1：信号梯度是通过有效扩散建立的。有大小依赖的调制的有效扩散系数，降解速率，或在小与大的芽基信号的敏感性。假设2：信号场是由传播波建立的，芽基细胞作为信号传播的中继单位。为了区分假设1和假设2，并阐明其机理基础，我们将：1）测量有效扩散系数和对小芽基和大芽基中信号传导因子的信号感知的敏感性2）创建报告子并测定可以驱动信号传播的信号传导的潜在传播波3）生成形态发生梯度缩放的数学模型，导出可测试的预测，4）最后，我们将通过实施TomoSeq结合功能测定来解决哪些分子调节肢体形态发生素的表达和活性结构域的大小。