Stat3/Cdc25a-dependent cell proliferation promotes embryonic axis extension during zebrafish gastrulation.
Stat3/Cdc25a-dependent cell proliferation promotes embryonic axis extension during zebrafish gastrulation.
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DOI：
10.1371/journal.pgen.1006564
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发表时间：
2017-02
期刊：
影响因子：
4.5
通讯作者：
Solnica-Krezel L
中科院分区：
文献类型：
--
作者：
Liu Y;Sepich DS;Solnica-Krezel L
脊椎动物原肠胚形成过程中，细胞增殖通常被认为是胚胎中轴前后延伸的重要因素。信号转导和转录激活因子3（Stat 3）是细胞增殖、存活和再生的保守控制因子，与人类脊柱侧凸、癌症和高IgE综合征相关。斑马鱼Stat 3被认为部分地通过促进Wnt/平面细胞极性（PCP）信号传导来控制会聚和伸展原肠胚形成运动，PCP信号传导是一种保守的中侧极化细胞行为的调节剂。在这里，使用斑马鱼stat 3无效突变体和药理学工具，我们证明了细胞增殖有助于前后胚胎轴的延伸。缺乏母体和合子Stat 3表达的斑马鱼胚胎表现出正常的会聚运动和平面细胞极性信号传导，但短暂的轴伸长缺陷，由于细胞数量不足，主要是由于细胞增殖减少和凋亡增加。在原肠胚形成过程中药理学抑制细胞增殖表型轴延长缺陷。Stat 3通过上调卵子发生过程中Cdc 25 a的表达来调节细胞增殖和轴延伸。因此，在stat 3突变体中恢复Cdc 25 a表达部分抑制了细胞增殖和原肠胚形成缺陷。在后期发育过程中，Stat 3突变斑马鱼表现出生长发育迟缓、脊柱侧凸、过度炎症和无法茁壮成长，为研究Stat 3在脊椎动物发育、再生和疾病中的功能提供了遗传工具。在脊椎动物胚胎发生过程中，细胞增殖、命运特化和细胞运动是将受精卵转化为具有头、躯干和尾巴的胚胎的关键过程。细胞增殖是由保守的调节因子包括Cdc 25 a的母体和合子功能协调的，并且通常被认为与胚胎轴伸长有关。Stat 3转录因子是一种已知的细胞增殖启动子，与人类脊柱侧凸、炎症和癌症有关。基于在斑马鱼胚胎发育过程中吗啉介导的Stat 3下调，Stat 3先前被提出通过平面细胞极性信号传导和未知的转录靶点来调节会聚和延伸细胞运动，从而使胚胎体变窄并从头到尾部分地伸长。在这里，我们报告说，斑马鱼突变体缺乏母亲和合子Stat 3表达表现出正常的收敛运动和平面细胞极性信号，但短暂的轴伸长缺陷，由于细胞数量不足，主要是由于细胞增殖减少和细胞死亡增加。因此，细胞增殖的药理学抑制也阻碍轴伸长。进一步的实验表明，Stat 3部分地通过在卵子发生过程中上调Cdc 25 a表达而刺激细胞增殖，从而促进头-尾轴的伸长.在后来的发育过程中，斑马鱼stat 3突变体表现出脊柱侧凸和炎症，可能为研究相关的人类疾病提供新的工具。
Cell proliferation has generally been considered dispensable for anteroposterior extension of embryonic axis during vertebrate gastrulation. Signal transducer and activator of transcription 3 (Stat3), a conserved controller of cell proliferation, survival and regeneration, is associated with human scoliosis, cancer and Hyper IgE Syndrome. Zebrafish Stat3 was proposed to govern convergence and extension gastrulation movements in part by promoting Wnt/Planar Cell Polarity (PCP) signaling, a conserved regulator of mediolaterally polarized cell behaviors. Here, using zebrafish stat3 null mutants and pharmacological tools, we demonstrate that cell proliferation contributes to anteroposterior embryonic axis extension. Zebrafish embryos lacking maternal and zygotic Stat3 expression exhibit normal convergence movements and planar cell polarity signaling, but transient axis elongation defect due to insufficient number of cells resulting largely from reduced cell proliferation and increased apoptosis. Pharmacologic inhibition of cell proliferation during gastrulation phenocopied axis elongation defects. Stat3 regulates cell proliferation and axis extension in part via upregulation of Cdc25a expression during oogenesis. Accordingly, restoring Cdc25a expression in stat3 mutants partially suppressed cell proliferation and gastrulation defects. During later development, stat3 mutant zebrafish exhibit stunted growth, scoliosis, excessive inflammation, and fail to thrive, affording a genetic tool to study Stat3 function in vertebrate development, regeneration, and disease. During vertebrate embryogenesis, cell proliferation, fate specification and cell movements are key processes that transform a fertilized egg into an embryo with head, trunk and tail. Cell proliferation is orchestrated by maternal and zygotic functions of conserved regulators including Cdc25a, and has generally been considered dispensable for embryonic axis elongation. Stat3 transcriptional factor, a known promoter of cell proliferation, is associated with human scoliosis, inflammation and cancer. Based on morpholino-mediated downregulation of Stat3 during zebrafish embryogenesis, Stat3 was previously proposed to regulate convergence and extension cell movements that narrow the embryonic body and elongate it from head to tail partially through planar cell polarity signaling and unknown transcriptional targets. Here, we report that zebrafish mutants lacking maternal and zygotic Stat3 expression exhibit normal convergence movements and planar cell polarity signaling, but transient axis elongation defect due to insufficient number of cells resulting largely from reduced cell proliferation and increased cell death. Accordingly, pharmacologic inhibition of cell proliferation also hinders axis elongation. Further experiments indicate that Stat3 promotes head- to -tail axis elongation by stimulating cell proliferation in part via upregulation of Cdc25a expression during oogenesis. During later development, zebrafish stat3 mutants exhibit scoliosis and inflammation, potentially affording a new tool to study related human diseases.