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种能力。 例如，蝾螈可以从截肢和脊髓横断中再生，而哺乳动物在很大程度上失去了再生重要身体部位的能力，并且神经组织再生能力极差。 目前尚不清楚为什么人类不能从脊髓切断中恢复，但部分原因是缺乏通过干/祖细胞增殖和随后的分化来替代受损细胞的能力。 为了理解再生，使用具有高再生能力的模型系统、中枢神经系统、干/祖细胞和测试基因功能的能力是至关重要的。 淡水扁虫是研究脑再生和干细胞生物学的理想模型系统。 Planarians有大量的成体干细胞，使他们能够再生任何因受伤而失去的身体部位，甚至可以在7天内再生整个头部，大脑和眼睛。 在这个提议中，我们假设头部再生可以分为两个过程。 首先是空间选择，使一个头与一个尾巴。 我们建议，这将使用众所周知的空间模式基因（HOX基因）。 第二，干细胞的增殖和分化必须使细胞成为新的大脑。 我们将测试神经模式基因的功能，看看在涡虫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个数据，说明Planarian干细胞使用哪些遗传途径在时间和空间上再生功能性大脑，并提供对大脑进化的分子见解。 我们的长期目标是利用涡虫的独特优势来了解成体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.