Biological and mathematical modeling of melanocyte development
Biological and mathematical modeling of melanocyte development
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DOI：
10.1242/dev.067447
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发表时间：
2011-09-15
期刊：
影响因子：
4.6
通讯作者：
Delmas, Veronique
中科院分区：
文献类型：
--
作者：
Luciani, Flavie;Champeval, Delphine;Delmas, Veronique
我们的目标是评估环境和遗传对胚胎发育过程中定向单细胞扩增/增殖的影响，使用成黑素细胞作为一个范例来模拟这种现象。成黑素细胞是一种特殊类型的细胞，在发育过程中表现出广泛的细胞增殖。然而，控制成黑色素细胞扩张的事件仍然知之甚少，由于对它们在各种皮肤隔室中的数量和分布的了解不足。我们发现，黑素细胞的扩张在空间和时间上都受到严格控制，胚胎之间的变化很小。我们建立了一个数学模型，反映了主要的细胞机制参与黑素细胞的扩张，包括增殖和迁移从真皮到表皮。与生物信息相关联，该模型允许计算成黑素细胞的倍增时间，揭示了真皮和表皮成黑素细胞具有短但不同的倍增时间。此外，在E8.5时，躯干创始黑素细胞的数量估计为16个，这是一个无法通过经典生物学方法计数的群体。我们还通过研究黑素细胞谱系中功能获得和丧失的β-连环蛋白突变体来评估遗传背景的重要性。我们发现，β-连环蛋白活性的任何改变，无论是阳性还是阴性，都会减少真皮和表皮成黑素细胞的增殖。最后，我们确定了在发育过程中，野生型和突变型胚胎中的真皮成黑素细胞库保持不变，这意味着与细胞分裂相关的特定控制机制确保了每次细胞分裂时有一半的细胞从真皮迁移到表皮。对黑色素母细胞扩张的建模揭示了细胞分裂、胚胎内的细胞定位和通过β-连环蛋白进行的适当反馈控制之间的新联系。
We aim to evaluate environmental and genetic effects on the expansion/proliferation of committed single cells during embryonic development, using melanoblasts as a paradigm to model this phenomenon. Melanoblasts are a specific type of cell that display extensive cellular proliferation during development. However, the events controlling melanoblast expansion are still poorly understood due to insufficient knowledge concerning their number and distribution in the various skin compartments. We show that melanoblast expansion is tightly controlled both spatially and temporally, with little variation between embryos. We established a mathematical model reflecting the main cellular mechanisms involved in melanoblast expansion, including proliferation and migration from the dermis to epidermis. In association with biological information, the model allows the calculation of doubling times for melanoblasts, revealing that dermal and epidermal melanoblasts have short but different doubling times. Moreover, the number of trunk founder melanoblasts at E8.5 was estimated to be 16, a population impossible to count by classical biological approaches. We also assessed the importance of the genetic background by studying gain-and loss-of-function beta-catenin mutants in the melanocyte lineage. We found that any alteration of beta-catenin activity, whether positive or negative, reduced both dermal and epidermal melanoblast proliferation. Finally, we determined that the pool of dermal melanoblasts remains constant in wild-type and mutant embryos during development, implying that specific control mechanisms associated with cell division ensure half of the cells at each cell division to migrate from the dermis to the epidermis. Modeling melanoblast expansion revealed novel links between cell division, cell localization within the embryo and appropriate feedback control through beta-catenin.