The Role of Fgf Signaling in Vertebrate Development

Fgf 信号传导在脊椎动物发育中的作用

基本信息

批准号：
10926004
负责人：
MARK B LEWANDOSKI
金额：
$ 71.23万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10926004
关键词：
Affect Apoptotic Behavior Biological Biology Cell Death Cell Maintenance Cell Survival Cells Collaborations Communities Complex Computer Models Congenital Abnormality Defect Dermis Development Disease Embryo Embryonic Development FGF17 gene Family Fibroblast Growth Factor Gene Expression Generations Genes Genetic Genetic Models Genetic study Genets Goals Growth Factor Gene Health Hindlimb Human Intermediate Mesoderm Kidney Knowledge Ligands Malignant Neoplasms Malignant neoplasm of prostate Measures Mesoderm Messenger RNA Modeling Molecular Morphogenesis Mus Muscle Paper Pathway interactions Play Positioning Attribute Process Proliferating Publications Publishing Role Series Signal Transduction Somites Technology Testicular Neoplasms Tissues Undifferentiated WNT Signaling Pathway Work allantois bone cancer therapy cardiogenesis cell behavior external genitalia fibroblast growth factor 18 genetic manipulation innovation insight male malignant breast neoplasm medical schools migration mouse genetics mutant nephrogenesis notch protein novel reproductive tract somitogenesis spine bone structure stem cells tool tumorigenesis vertebra body vertebrate embryos

项目摘要

The long term goal of this project is to understand how an important family of signaling ligands, called Fibroblast Growth Factors (FGFs), control a wide spectrum of cell biological behaviors such as proliferation, cell death, migration, stem cell maintenance and gene expression. In particular, we use complex mouse genetics to understand the role of FGF signaling in mesodermal lineages with a special emphasis on extension of the body axis and formation of somites (segmented mesodermal segments that are the building blocks of vertebrate muscle, dermis and vertebral bodies). Our work has made clear that genetic redundancy is an important aspect of this biology; therefore all work in this project emerges from an effort to comprehensively characterize the genetic redundancy of FGF signaling in the mesodermal lineage. Such work is relevant to many cases of cancer where more than one FGF gene may be damaged. To achieve this, we have generated and characterized important Cre mouse lines, which are tools that allow the control of gene expression in the early embryo. These include TCre (expressed in the early emerging nascent mesoderm; see Development. 132: 3859-71. ), TCreERT2 (active in emerging nascent mesoderm at all embryonic stages; see PLoS ONE. 8: e62479) and Tbx4-Cre (expressed in a posterior mesodermal domain that includes the allantois, hindlimb, and external genitalia; see Dev Dyn. 240: 2290-300. doi: 10.1002/dvdy.22731). TCre, in particular, has had a major impact on the field, being essential in over 50 publications. For example, both TCre and TCreERT2 have important in a collaborative effort to demonstrate that Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension (Hum Mol Genet. 2014 Jul 31. pii: ddu397). Besides providing the mouse genetics community with valuable mouse lines, this project has yielded papers that document our major insights regarding FGF signaling in the early embryo. We published that Fgf8 not required for somitogenesis, although a body of high-profile work had placed it in a central position in current models. However, in collaboration with NCI colleague, Alan Perantoni, we demonstrated that Fgf8 was essential for development of the kidney and male reproductive tract (Development. 132: 3859-71, Development. 138: 5369-78). A feature of these mutants was aberrant cell death due to loss of Fgf8 signaling. This past year, we published a study, showing we can restore cell survival to such mutants, by removing the pro-apoptotic genes, Bax and Bak. This genetic manipulation restores some measure of kidney development, but nephrogenesis is not normal, revealing new insights into Fgf8 function in this process (Differentiation, 2023, 130:7-15). We showed that Fgf8, together with Fgf4, are required for essential aspects of somitogenesis: expression of oscillating gene domains, WNT pathway genes and markers of undifferentiated presomitic mesoderm (Proc Natl Acad Sci U S A. 108: 4018-23). By examining FGF mutants in which we genetically restored WNT signaling, we demonstrated that FGF signaling operates independently of WNT signaling in this process. The functional redundancy that we uncovered has implications for cancer as both FGFs have been found to be aberrantly active in testicular tumors. In recent studies we have delved deeper into this work and have shown that Fgf4 mutants (but not Fgf8 mutants) display a range of vertebral defects that model a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations. A key innovation in this work is our adaption of computational modeling to generate embryonic volumetric subsets of the embryo. We then quantify mRNA levels of key target genes, affected by the loss of Fgf4 signaling, within these volumes (eLife 2020;9:e55608. DOI: https://doi.org/10.7554/eLife.55608). We applied this technical innovation in a collaborative study published with the Kwon lab at Johns Hopkins Medical School on the role of WNT signaling in heart development (Proc Natl Acad Sci U S A., 2023, 120(4):e2217687120). In another recent publication, we demonstrated that the Fgf8 subfamily (Fgf8, Fgf17 and Fgf18) are required for closing the ventral body wall in the vertebrate embryo. Defects in this process are a major class of human birth defect and a significant health burden (Development (2020) 147, dev189506. doi:10.1242/dev.189506). We are continuing to study genetic redundancy in FGF signaling in several aspects of embryonic development. We are currently focusing on two aspects of development: generation of the promitive streak, which generates all embryonic mesoderm and differentiation of the somite into its derivative lineages (muscle and bone).

该项目的长期目标是了解重要的信号配体系列（称为成纤维细胞生长因子（FGF））如何控制各种细胞生物学行为，例如增殖，细胞死亡，迁移，干细胞维持和基因表达。特别是，我们使用复杂的小鼠遗传学来了解FGF信号在中胚层谱系中的作用，特别强调了身体轴的扩展和体子的形成（分段的中胚片段，这些段是椎骨肌肉，真皮和椎体的构成，。我们的工作清楚地表明，遗传冗余是该生物学的重要方面。因此，该项目中的所有工作都从全面表征中胚层谱系中FGF信号的遗传冗余的努力中出现。这种工作与许多癌症病例有关，其中一个以上的FGF基因可能损坏。为了实现这一目标，我们已经生成并表征了重要的CRE小鼠系，它们是允许在早期胚胎中控制基因表达的工具。其中包括TCRE（在早期新生的中胚层中表达；请参见开发。132：3859-71。），TCREERT2（在所有胚胎阶段都活跃于新兴的新生中胚层；请参见PLOSONE。8：E62479）和TBX4-CRE（表达在TBX4-CRE中（表示）后胚层领域，包括艾兰蒂瓦（Allantois），后肢和外部生殖器；特别是TCRE对该领域产生了重大影响，在50多个出版物中至关重要。例如，TCRE和TCREERT2在协作的努力中都很重要，以证明WNT5A/ROR2信号传导通过控制中间中胚层扩展来调节肾脏形态发生（Hum MolGenet。2014Jul31。PII。PII：DDU397）。除了为小鼠遗传学界提供有价值的鼠标线外，该项目还产生了论文，这些论文记录了我们关于早期胚胎中FGF信号的主要见解。我们发表了说，尽管备受瞩目的工作使它处于当前模型中的中心位置，但FGF8并不需要。但是，与NCI同事Alan Perantoni合作，我们证明了FGF8对于肾脏和男性生殖道的发展至关重要（开发。132：3859-71，Development。138：5369-78）。这些突变体的一个特征是由于FGF8信号传导的丧失而导致的细胞死亡异常。在过去的一年中，我们发表了一项研究，表明我们可以通过去除促凋亡基因，巴克斯和巴克来恢复细胞存活。这种遗传操纵恢复了肾脏发育的某种度量，但是肾脏发生不正常，在此过程中揭示了对FGF8功能的新见解（分化，2023，130：7-15）。我们表明，FGF8与FGF4一起是体质发生的基本方面所必需的：振荡基因结构域的表达，Wnt途径基因和未分化的前序中胚层的标志物（Proc Natl Acad Sci Sci Sci A. 108：4018-23）。通过检查我们从基因恢复的Wnt信号传导的FGF突变体，我们证明了FGF信号在此过程中独立于Wnt信号传导。我们发现的功能冗余对癌症具有影响，因为两种FGF在睾丸肿瘤中都异常活跃。在最近的研究中，我们对这项工作进行了更深入的研究，并表明FGF4突变体（但不是FGF8突变体）显示出一系列椎骨缺陷，这些缺陷模拟了由缺陷型缺口振荡引起的人类分割缺陷的光谱。这项工作中的一个关键创新是我们对计算建模的改编，以生成胚胎的胚胎体积子集。然后，我们量化了在这些体积中受FGF4信号传导损失影响的关键靶基因的mRNA水平（Elife 2020; 9：e55608。doi：https：//doi.org/10.7554/10.7554/elife.55608）。我们在约翰·霍普金斯医学院（Johns Hopkins Medical School）的一次合作研究中应用了这项技术创新，该研究涉及Wnt信号在心脏发展中的作用（Proc Natl Acad Sci u S A.，2023，2023，120，4）：E2217687120）。在最近的另一份出版物中，我们证明了FGF8亚家族（FGF8，FGF17和FGF18）是要关闭脊椎动物胚胎中腹侧身体壁的必需。此过程中的缺陷是人类出生缺陷和重大健康负担的主要类别（开发（2020）147，DEV189506。DOI：10.1242/dev.189506）。我们正在继续研究胚胎发育的几个方面中FGF信号传导中的遗传冗余。我们目前正在关注发展的两个方面：股关系的产生，该条纹生成所有胚胎中胚层和分化体内的衍生物（肌肉和骨骼）。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmental biology: extending the limb and body with vectors and scalars.

发育生物学：用矢量和标量延伸肢体和身体。

DOI：
10.1016/j.cub.2010.11.023
发表时间：
2011
期刊：
Current biology : CB
影响因子：
0
作者：
Lewandoski,Mark;Mackem,Susan
通讯作者：
Mackem,Susan

Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension.

非经典 Wnt5a/Ror2 信号通过控制中间中胚层延伸来调节肾脏形态发生。

DOI：
10.1093/hmg/ddu397
发表时间：
2014
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Yun,Kangsun;Ajima,Rieko;Sharma,Nirmala;Costantini,Frank;Mackem,Susan;Lewandoski,Mark;Yamaguchi,TerryP;Perantoni,AlanO
通讯作者：
Perantoni,AlanO

A CO-FISH assay to assess sister chromatid segregation patterns in mitosis of mouse embryonic stem cells.

DOI：
10.1007/s10577-013-9358-8
发表时间：
2013-05
期刊：
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology
影响因子：
0
作者：
Sauer S;Burkett SS;Lewandoski M;Klar AJ
通讯作者：
Klar AJ

A novel role of the organizer gene Goosecoid as an inhibitor of Wnt/PCP-mediated convergent extension in Xenopus and mouse.

DOI：
10.1038/srep43010
发表时间：
2017-02-21
期刊：
Scientific reports
影响因子：
4.6
作者：
Ulmer B;Tingler M;Kurz S;Maerker M;Andre P;Mönch D;Campione M;Deißler K;Lewandoski M;Thumberger T;Schweickert A;Fainsod A;Steinbeißer H;Blum M
通讯作者：
Blum M

Broad mesodermal and endodermal deletion of Nodal at postgastrulation stages results solely in left/right axial defects.