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首页> 外文学位 >SALL4 and PLZF mediate genomic actions of GDNF signaling in spermatogonial stem cells.
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SALL4 and PLZF mediate genomic actions of GDNF signaling in spermatogonial stem cells.

机译：SALL4和PLZF介导精原干细胞中GDNF信号传导的基因组作用。

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摘要

Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout adulthood through balanced self-renewing and differentiating fate decisions, yet little is known about how these fate decisions are controlled. Glial cell-lined derived neurotrophic factor (GDNF) is an essential growth factor that promotes SSC survival and self-renewal through activation of signaling cascades which in turn leads to changes in expression of downstream genes. However, the transcriptional mechanisms mediating gene expression in response to GDNF was unknown. To potentially address this question we turned to the two transcription factors Sal-like 4 (SALL4) and zinc finger and BTB domain containing 16 (ZBTB16, aka: PLZF), which are known to be required for normal SSC self-renewal and differentiation. Little was known on how PLZF and SALL4 exert regulatory influence in SSCs so we performed a ChIP-Seq analysis in THY1+ spermatogonia, which are enriched for SSCs, to identify the binding repertoires of PLZF and SALL4. Subsequent gene ontology (GO) analysis of these binding repertoires identified an over-representation of GDNF-responsive genes. That led us to hypothesize that the changes in gene expression of GDNF-responsive genes was mediated by the binding and transcriptional regulation of PLZF and SALL4. Targeted knockdown of each transcription factor in THY1+ spermatogonia under steady state conditions revealed that SALL4 and PLZF are required to maintain mRNA levels of putative target genes, suggesting that transcription factor binding to these genes at the positions identified by ChIP-Seq activates their transcription. To confirm if the observed transcriptional response to GDNF was mediated by PLZF and SALL4 we evaluated THY1+ spermatogonia cultures deficient for PLZF and SALL4 and measured transcriptional response to GDNF stimulating conditions. Tandem knockdown and EU labeling experiments revealed that not all GDNF-responsive genes rely on PLZF or SALL4 to induce a response. SALL4 appeared to potentially have more of a role in mediating the response in GDNF-stimulated genes, like Egr3, while loss of Plzf suggested it potentially mediates the transcriptional response in GDNF-inhibited genes.
机译：精原干细胞（SSC）通过平衡的自我更新和差异化的命运决定维持整个成年期的精子发生，但对如何控制这些命运决定的知之甚少。胶质细胞内衬衍生神经营养因子（GDNF）是必需的生长因子，可通过激活信号级联反应来促进SSC存活和自我更新，进而导致下游基因表达的改变。但是，调解基因响应GDNF的转录机制是未知的。为了潜在地解决这个问题，我们转向两个转录因子Sal-like 4（SALL4）和含16的锌指和BTB结构域（ZBTB16，aka：PLZF），已知这是正常SSC自我更新和分化所必需的。关于PLZF和SALL4如何在SSC中发挥调控作用知之甚少，因此我们对富含SSC的THY1 +精原细胞进行了ChIP-Seq分析，以鉴定PLZF和SALL4的结合库。这些绑定目录的后续基因本体（GO）分析确定了GDNF响应基因的过度表达。这使我们假设GDNF反应基因的基因表达变化是由PLZF和SALL4的结合和转录调控介导的。在稳态条件下有针对性地敲低THY1 +精原细胞中每个转录因子的结果表明，需要SALL4和PLZF来维持推定靶基因的mRNA水平，这表明在ChIP-Seq鉴定的位置上与这些基因结合的转录因子会激活它们的转录。为了确认观察到的对GDNF的转录反应是否由PLZF和SALL4介导，我们评估了缺乏PLZF和SALL4的THY1 +精原细胞培养物，并测量了对GDNF刺激条件的转录反应。串联敲除和EU标记实验表明，并非所有GDNF应答基因都依赖PLZF或SALL4诱导应答。 SALL4似乎可能在介导GDNF刺激的基因（如Egr3）的应答中发挥更大的作用，而Plzf的丢失则表明它可能介导GDNF抑制的基因的转录应答。

著录项

  • 作者

    Lovelace, Dawn L.;

  • 作者单位

    The University of Texas at San Antonio.;

  • 授予单位 The University of Texas at San Antonio.;
  • 学科 Biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 152 p.
  • 总页数 152
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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