Spatial re-patterning of stem cell lineages during brain regeneration in freshwater planarians

大多数生物在受伤后至少有一定的再生能力，尽管很明显，许多物种在进化过程中失去了这一能力。例如，蝾螈可以通过截肢和脊髓横断再生，而哺乳动物已经在很大程度上失去了再生身体重要部位的能力，而且神经组织的再生能力非常差。目前尚不清楚为什么人类无法从脊髓切断后恢复，但部分障碍是缺乏通过干细胞/祖细胞增殖和随后的分化来替换受损细胞的能力。为了理解再生，关键是使用具有高再生能力的模型系统、中枢神经系统、干细胞/祖细胞以及测试基因功能的能力。淡水浮游动物是研究脑再生和干细胞生物学的理想模型系统。浮游生物拥有大量的成体干细胞，这使它们能够再生任何因受伤而丢失的身体部位，甚至可以在7天内再生整个头部、大脑和眼睛。在这个方案中，我们假设头部再生可以分为两个过程。首先是头对尾的空间选择。我们建议这将使用众所周知的空间模式基因(HOX基因)。其次，干细胞的增殖和分化必须使新脑的细胞。我们将测试神经模式基因的功能，看看在脊椎动物大脑再生过程中的遗传机制是否与其他系统中大脑发育过程中的遗传机制相似。这项工作将提供第一批数据，关于基因路径被浮游动物干细胞用来在时间和空间上再生一个功能正常的大脑，以及提供对大脑进化的分子洞察力。我们的长期目标是利用浮游生物提供的独特优势，学习成年干细胞如何协调空间模式和谱系分化，以正确地替换缺失的组织。

Most organisms have at least some capacity to regenerate following injury, although it is clear that many species have lost this during evolution. For example a newt can regenerate from limb amputations and spinal cord transections, while mammals have largely lost the ability to regenerate significant body parts and are extremely poor regenerators of nervous tissue. It is currently unknown why humans cannot recover from severing of the spinal cord, but part of the block is the lack of ability to replace the damaged cells via stem/progenitor cell proliferation and subsequent differentiation. To understand regeneration, it is critical to use a model system that has high regeneration capacity, a central nervous system, stem/progenitor cells, and the ability to test gene function. The freshwater planarian (flatworm, Lophotrochozoan) is an ideal model system to study brain regeneration and stem cell biology. Planarians have a large population of adult stem cells which allow them to regenerate any missing body part that is lost to injury, and can even regenerate an entire head, brain, and eyes in the span of 7 days. In this proposal, we hypothesize that head regeneration can be broken down into 2 processes. First is the spatial choice to make a head vs. a tail. We propose that this will use well-known spatial patterning genes (HOX genes). Second, stem cell proliferation and differentiation must make the cells of the new brain. We will test the function of neural patterning genes to see whether genetic mechanisms during planarian brain regeneration are similar to the genetic mechanisms during brain development in other systems. This work will provide the first data on which genetic pathways are used by planarian stem cells to regenerate a functional brain in both time and space as well as provide molecular insight into brain evolution. Our long-term goal is to use the unique advantages planarians offer to learn how adult stem cells coordinate spatial patterning and lineage differentiation to correctly replace missing tissues.