Mechanisms underlying establishment of regeneration competence

再生能力建立的机制

基本信息

批准号：
10487124
负责人：
Erin Davies
金额：
$ 60.39万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Planarian regeneration requires adult pluripotent stem cells, the source of all new tissues, and instructive cues from pre-existing tissues to re-establish polarity, patterning, and orchestrate differentiation of missing cell types. When and how embryos acquire regenerative abilities was not known. We discovered that regeneration competence is an emergent developmental property that seems to be limited by the development of somatic tissue(s) necessary for context-dependent regulation of stem cell dynamics after injury. We observe stage- and axial position-dependent effects on regenerative abilities late in embryogenesis, culminating in production of a fully regeneration-competent animal at hatching. Regeneration-incompetent animals, while able to regenerate posterior body structures, were incapable of regenerating new anterior (head) tissue. Ongoing work suggests that stem cell specification is not rate-limiting for establishment of regeneration competence: stem cells were present and cycling in regeneration-incompetent animals. We discovered that failure to reset the anterior-posterior axis underlies the head regeneration defect. RNAi knock-down of the Wnt pathway effector Beta-catenin-1 induced precocious head formation in regeneration-incompetent embryos, suggesting that high Wnt pathway activity inhibits anterior regeneration. Consistent with this result and in contrast to what was observed in regeneration-competent embryos, regeneration-incompetent embryos did not express Wnt pathway inhibitors, like notum, in anterior-facing blastemas. We are currently investigating how development of tissues that are transcriptionally responsive to wounding, including the body wall musculature, impinge on axial polarity re-establishment and acquisition of regeneration competence. Our results suggest that regeneration is regulated hierarchically, with master regulators of axial polarity governing regional patterning and organogenesis.

Planarian再生需要成年多能干细胞，所有新组织的来源，以及从预先存在的组织到重新建立极性，模式和编排丢失细胞类型的分化的启发性线索。胚胎何时以及如何获得再生能力。我们发现，再生能力是一种新兴的发育特性，似乎受到损伤后干细胞动态所必需的体细胞组织的发展而受到限制。我们观察到胚胎发生后期对再生能力的阶段和轴向位置依赖性影响，最终导致孵化时完全再生能力的动物的产生。再生不足的动物虽然能够再生后体结构，但无法再生新的前（头）组织。正在进行的工作表明，干细胞规范不是建立再生能力的限制：存在干细胞并在不足的动物中骑自行车。我们发现未能重置前后轴是头部再生缺陷的基础。 Wnt途径效应子β-catenin-1诱导重生 - 功能不足的胚胎诱导早熟的头部形成的RNAi敲低，这表明高Wnt途径活性抑制了前再生。与该结果一致，与在竞争性胚胎中观察到的相反，再生胚胎不足的胚胎在朝前的胚芽中没有表达Wnt途径抑制剂，例如Notum。我们目前正在研究如何响应伤害的组织的发展，包括身体壁肌肉组织，影响轴向极性重新建立和再生能力的获得。我们的结果表明，再生在层次上受到调节，轴向极性管理区域模式和器官发生的主要调节剂。