The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch
The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch
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DOI：
10.1073/pnas.1005998107
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发表时间：
2010-10-26
影响因子：
11.1
通讯作者：
Drummond, Iain A.
中科院分区：
文献类型：
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作者：
Hellman, Nathan E.;Liu, Yan;Drummond, Iain A.
纤毛对正常器官功能和发育模式至关重要，但它们在损伤和再生反应中的作用尚不清楚。为了探讨纤毛在损伤中的作用，我们分析了纤毛基因转录调节因子foxj 1在组织损伤和肾囊肿形成中的作用。斑马鱼foxj 1a，而不是foxj 1b，迅速诱导上皮扩张和拉伸，肾囊肿形成，急性肾损伤庆大霉素，脊髓细胞挤压损伤。阻塞诱导的foxj 1a上调不被放线菌酮抑制，这表明foxj 1a是上皮损伤的主要反应基因。Foxj 1在小鼠囊性肾病上皮细胞[jck/jck（nek 8）和Ift 88 Tg 737 Rpw（-/-）]中以及在对肾缺血再灌注损伤的反应中也显著上调。阻塞的斑马鱼前肾小管引起纤毛跳动率的迅速增加，与扩张的小管直径和上皮拉伸密切相关。斑马鱼foxj 1a是纤毛运动特别需要的。foxj 1a在阻塞小管中表达增强诱导纤毛运动靶基因efhc 1，tektin 1和dnahc 9。FOXJ 1A缺陷的胚胎不能上调EfHC 1、Tektin-1和DNAHC 9，并且在阻塞后不能维持增强的纤毛搏动速率，从而确定FOXJ 1在损伤后调节纤毛功能中的重要作用。这些研究表明，激活的Foxj 1转录网络的ciliogenic基因是一种进化保守的多种形式的组织损伤的反应，并强调增强纤毛功能作为一个以前未表征的组成部分的器官稳态。
Cilia are essential for normal organ function and developmental patterning, but their role in injury and regeneration responses is unknown. To probe therole of cilia in injury, we analyzed the function of foxj1, a transcriptional regulator of cilia genes, in response to tissue damage and renal cyst formation. Zebrafish foxj1a, but not foxj1b, was rapidly induced in response to epithelial distension and stretch, kidney cyst formation, acute kidney injury by gentamicin, and crush injury in spinal cord cells. Obstruction-inducedup-regulation of foxj1a was not inhibited by cycloheximide, identifying foxj1a as a primary response gene to epithelial injury. Foxj1 was also dramatically up-regulated in murine cystic kidney disease epithelia [jck/jck ( nek8) and Ift88Tg737Rpw(-/-)] as well as in response to kidney ischemia-reperfusion injury. Obstruction of the zebrafish pronephric tubule caused a rapid increase in cilia beat rate that correlated tightly with expanded tubule diameter and epithelial stretch. Zebrafish foxj1a was specifically required for cilia motility. Enhanced foxj1a expression in obstructed tubules induced ciliamotility target genes efhc1, tektin1, and dnahc9. foxj1a-deficient embryos failed to up-regulate efhc1, tektin-1, and dnahc9 and could not maintain enhanced cilia beat rates after obstruction, identifying an essential role for foxj1 in modulating cilia function after injury. These studies reveal that activation of a Foxj1 transcriptional network of ciliogenic genes is an evolutionarily conserved response to multiple forms of tissue damage and highlight enhanced cilia function as a previously uncharacterized component of organ homeostasis.