Identification and characterization of FGF target genes

FGF 靶基因的鉴定和表征

• 批准号: 10926182
• 负责人: MARK B LEWANDOSKI
• 金额: $ 39.57万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926182
• 关键词: Address; Anatomy; Apoptotic; Behavior Control; Cardiac; Cell Communication; Cell Death; Cells; Chronic Kidney Failure; Cis-Acting Sequence; Compensation; Connective Tissue; Data; Defect; Dermis; Development; Disease; Dorsal; Embryo; Embryonic Development; Family member; Fibroblast Growth Factor; Future; GBX1 gene; Gene Expression; Gene Expression Profiling; Gene Family; Gene Targeting; Genes; Genetic; Goals; Growth Factor Gene; Human; Interneurons; Knowledge; Label; Malignant Neoplasms; Mantle Zone; Mesoderm; Messenger RNA; Modeling; Molecular; Motor Neurons; Muscle; Mutant Strains Mice; Pathology; Pathway interactions; Periodicity; Play; Proliferating; Reaction; Regulation; Regulatory Element; Role; Segmentation Clock Pathway; Signal Pathway; Signal Transduction; Somites; Spinal Cord; Trans-Activators; Transcription Repressor; Vertebral column; Work; angiogenesis; bone; cell behavior; combinatorial; insight; member; migration; mutant; neurogenesis; notch protein; novel; prevent; somitogenesis; spine bone structure; synergism; transcription factor

To address the deficiency in our knowledge of what genes respond to FGF signaling, we have an ongoing project to molecularly define FGF targets genes, as well as their function and regulation. In past work, we and others have identified the transcription factors encoded by Gbx1 and Gbx2 as FGF targets. Recently we investigated the functional relationship between Gbx family members in the developing spinal cord using combinatorial Gbx mouse mutants. We showed that each Gbx gene is upregulated if the other is absent. Additionally, Gbx genes regulate development of a subset of PAX2+ dorsal inhibitory interneurons. Also, expansion of proliferative cells into the anatomically defined mantle zone occurs in Gbx mutants. Lastly, our data shows a marked increase in apoptotic cell death in the ventral spinal cord of Gbx mutants during mid-embryonic stages. While our studies reveal that both members of the Gbx gene family are involved in development of subsets of PAX2+ dorsal interneurons and survival of ventral motor neurons, Gbx1 and Gbx2 are not sufficient to genetically compensate for the loss of one another. Thus, our studies provide novel insight to the relationship harbored between Gbx1 and Gbx2 in spinal cord development (J Dev Biol. 2020. PMID: 32244588). In current work, we demonstrate that the Hes7 transcriptional repressor is apparently a direct target of Fgf4 signaling. During vertebrate development, the presomitic mesoderm (PSM) is periodically segmented into somites, which will form the segmented vertebral column and associated muscle, connective tissue, and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. We examined mouse mutants lacking only Fgf4 or Fgf8, which we previously demonstrated act redundantly to prevent PSM differentiation. Fgf8 is not required for somitogenesis, but Fgf4 mutants display a range of vertebral defects. Analyzing gene expression with spatial model-based quantification of mRNAs fluorescently labeled by hybridization chain reaction, we show that FGF4 controls Notch pathway oscillations through the transcriptional repressor, HES7. We support this hypothesis by demonstrating a genetic synergy between Hes7 and Fgf4, but not with Fgf8. Thus, we establish Fgf4 as an essential Notch oscillation regulator and potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations. (eLife 2020 Nov 19;9:e55608. doi: 10.7554/eLife.55608.) Future work focuses on what regulatory elements within the Hes7 gene are responsive to Fgf4 signals.

为了解决我们对哪些基因响应 FGF 信号传导的了解不足，我们正在进行一个项目，从分子角度定义 FGF 靶基因及其功能和调控。在过去的工作中，我们和其他人已经将 Gbx1 和 Gbx2 编码的转录因子确定为 FGF 靶标。最近，我们使用组合 Gbx 小鼠突变体研究了发育中脊髓中 Gbx 家族成员之间的功能关系。我们发现，如果另一个 Gbx 基因缺失，则每个 Gbx 基因都会上调。此外，Gbx 基因调节 PAX2+ 背侧抑制性中间神经元子集的发育。此外，在 Gbx 突变体中，增殖细胞会扩展到解剖学上定义的地幔区。最后，我们的数据显示，Gbx 突变体在胚胎中期的腹侧脊髓中凋亡细胞死亡显着增加。虽然我们的研究表明 Gbx 基因家族的两个成员都参与 PAX2+ 背侧中间神经元亚群的发育和腹侧运动神经元的存活，但 Gbx1 和 Gbx2 不足以从遗传上补偿彼此的损失。因此，我们的研究为脊髓发育中 Gbx1 和 Gbx2 之间的关系提供了新的见解 (J Dev Biol. 2020. PMID: 32244588)。在目前的工作中，我们证明 Hes7 转录阻遏蛋白显然是 Fgf4 信号传导的直接目标。在脊椎动物发育过程中，前体中胚层（PSM）周期性地分裂成体节，体节将形成分段的脊柱和相关的肌肉、结缔组织和真皮。体节发生的周期性由振荡Notch 活动的分段时钟调节。我们检查了仅缺乏 Fgf4 或 Fgf8 的小鼠突变体，我们之前证明它们可以冗余地阻止 PSM 分化。 Fgf8 不是体细胞发生所必需的，但 Fgf4 突变体表现出一系列椎骨缺陷。通过基于空间模型的杂交链式反应荧光标记的 mRNA 定量分析基因表达，我们发现 FGF4 通过转录抑制子 HES7 控制 Notch 通路振荡。我们通过证明 Hes7 和 Fgf4 之间（但不与 Fgf8）之间的遗传协同作用来支持这一假设。因此，我们将 Fgf4 确定为重要的 Notch 振荡调节因子，并且在由有缺陷的 Notch 振荡引起的一系列人类椎骨分段缺陷中具有潜在的重要作用。 （eLife 2020 年 11 月 19 日；9:e55608。doi: 10.7554/eLife.55608。）未来的工作重点是 Hes7 基因内的哪些调控元件对 Fgf4 信号有反应。

项目成果

Inactivation of Fgf3 and Fgf4 within the Fgf3/Fgf4/Fgf15 gene cluster reveals their redundant requirement for mouse inner ear induction and embryonic survival.

• DOI: 10.1002/dvdy.435
• 发表时间: 2022-05
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists

Fgf4 maintains Hes7 levels critical for normal somite segmentation clock function.

• DOI: 10.7554/elife.55608
• 发表时间: 2020-11-19
• 期刊: eLife
• 影响因子: 7.7
• 作者: Anderson MJ;Magidson V;Kageyama R;Lewandoski M
• 通讯作者: Lewandoski M

Fgf8 promotes survival of nephron progenitors by regulating BAX/BAK-mediated apoptosis.

Fgf8 通过调节 BAX/BAK 介导的细胞凋亡来促进肾单位祖细胞的存活。

• DOI: 10.1016/j.diff.2022.12.001
• 发表时间: 2023
• 期刊: Differentiation; research in biological diversity
• 作者: Anderson,MatthewJ;Misaghian,Salvia;Sharma,Nirmala;Perantoni,AlanO;Lewandoski,Mark
• 通讯作者: Lewandoski,Mark