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.

为了解决我们了解哪些基因对FGF信号的反应的不足，我们有一个持续的项目来分子定义FGF靶标基因及其功能和调节。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目标。最近，我们研究了使用组合GBX小鼠突变体在发育中的脊髓中GBX家族成员之间的功能关系。我们表明，如果不存在另一个GBX基因，则每个GBX基因都上调。此外，GBX基因调节PAX2+背抑制性中间神经元的子集的发展。同样，在GBX突变体中，增殖细胞扩展到解剖学定义的地幔区域发生。最后，我们的数据表明，在胚胎中期阶段，GBX突变体的腹侧脊髓中凋亡细胞死亡显着增加。尽管我们的研究表明，GBX基因家族的两个成员都参与了PAX2+背膜中间神经元子集的发展以及腹运动神经元的存活，GBX1和GBX2不足以依赖彼此的损失。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 DevBiol。2020。PMID：32244588）。在当前的工作中，我们证明HES7转录阻遏物显然是FGF4信号传导的直接目标。在脊椎动物发育过程中，定期将前中胚层（PSM）分割成节，这将形成分段的椎骨柱和相关的肌肉，结缔组织和真皮。体内生成的周期性受振荡活性的分割时钟的调节。我们检查了仅缺乏FGF4或FGF8的小鼠突变体，以前我们证明了这些突变体，以防止PSM分化。 fgf8不需要，但FGF4突变体显示一系列椎骨缺陷。用基于空间模型的杂交链反应标记的mRNA荧光标记的MRNA荧光标记的基因表达，我们表明FGF4通过转录阻遏物Hes7控制Notch途径振荡。我们通过证明HES7和FGF4之间的遗传协同作用来支持这一假设，而不是FGF8。因此，我们将FGF4建立为必不可少的缺口振荡调节剂，并且在由缺陷型缺口振荡引起的椎骨的一系列人类分割缺陷中可能很重要。 （Elife 2020年11月19日； 9：E55608。DOI：10.7554/Elife.55608。）未来的工作重点介绍HES7基因中的监管元素对FGF4信号的反应。

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