The Role of Fgf Signaling in Vertebrate Development

贺龙这个项目的目标是了解一个重要的信号配体家族，即成纤维细胞生长因子(FGFs)是如何控制广泛的细胞生物学行为的，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成纤维细胞生长因子信号在中胚层谱系中的作用，特别强调体轴的延伸和体节的形成(节段性中胚层片段是脊椎动物肌肉、真皮和椎体的基石)。我们的工作表明，遗传冗余是这一生物学的一个重要方面；因此，这个项目的所有工作都是为了全面表征中胚层谱系中成纤维细胞生长因子信号的遗传冗余。这项工作与许多癌症病例有关，在这些病例中，可能有不止一个成纤维细胞生长因子基因受损。为了实现这一点，我们创造了重要的Cre小鼠品系并对其进行了表征，这些品系是允许控制早期胚胎中基因表达的工具。其中包括TCre(在早期初生的中胚层中表达；见发育。132：3859-71。)，TCreERT2(在所有胚胎阶段活跃于新生的中胚层；见PLoS one。8：E62479)和Tbx4-Cre(在包括尿囊、后肢和外生殖器的后中胚层区域表达；见Dev dyn。240：2290-300。DOI：10.1002/dvdy.22731)。尤其是TCRE对这一领域产生了重大影响，在30多份出版物中发挥了重要作用。例如，TCre和TCreERT2在证明Wnt5a/Ror2信号通过控制中间中胚层延伸(Hum Mol Genet)来调节肾脏形态发生的合作努力中都具有重要意义。2014年7月31日PII：ddu397)除了为小鼠遗传学社区提供有价值的小鼠品系外，该项目还发表了一些论文，记录了我们对早期胚胎中成纤维细胞生长因子信号的主要见解。我们发表了Fgf8在体细胞发生中不是必需的，尽管一系列高调的工作已经将它放在了当前模型的中心位置。然而，在与NCI的同事Alan Perantoni的合作中，我们证明了Fgf8对于肾脏和男性生殖道的发育是必不可少的。132：3859-71，发展。138：5369-78)。我们发现，FGF8和FGF4一起是体细胞发生所必需的：振荡基因结构域、WNT途径基因和未分化的有丝分裂前中胚层的标记的表达(《学报》，S，A。108：4018-23)。通过研究我们通过基因恢复WNT信号的成纤维细胞生长因子突变体，我们证明了在这个过程中，成纤维细胞生长因子信号独立于WNT信号起作用。我们发现的功能冗余与癌症有关，因为这两种FGFs在睾丸肿瘤中都被发现异常活跃。此外，这种冗余对进化有影响，因为相同的FGFs在肢体发育中起着补偿作用。我们正在继续研究成纤维细胞生长因子信号中的遗传冗余在胚胎发育的几个方面。例如，我们最近证明了Fgf3信号在神经管关闭中是重要的，这是一项关于最常见的出生缺陷之一脊柱裂(PLoS Genet)的重要研究。12(5)：e1006018；创世纪54：91-8)。我们正在研究Fgf4和Fgf8在体节分化为其衍生谱系(肌肉和骨骼)中的作用。在这个项目的另一部分，我们正在研究这些FGFs在尿囊发育中的作用，尿囊是一种形成胎盘血管和脐带的组织。在人类中，这种组织不能正常发育是妊娠丢失的许多方面的基础。

he 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 30 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). 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. Furthermore this redundancy has implications for evolution as the same FGFs play compensatory roles in limb development. We are continuing to study genetic redundancy in FGF signaling in several aspects of embryonic development. For example, we recently showed that Fgf3 signaling is important in neural tube closure, an important study that concerns one of the most common birth defects, spina bifida (PLoS Genet. 12(5):e1006018; Genesis 54:91-8). We are investigating the role of Fgf4 and Fgf8 in the differentiation of the somite into its derivative lineages (muscle and bone). In another part of this project, we are studying the role of these Fgfs in development of the allantois, a tissue that gives rise to the placental blood vessels and the umbilical cord. In human, failure of this tissue to develop properly underlies many aspects of pregnancy loss.