The Role of Fgf Signaling in Vertebrate Development

Fgf 信号传导在脊椎动物发育中的作用

• 批准号: 7965266
• 负责人: MARK B LEWANDOSKI
• 金额: $ 40.9万
• 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/7965266
• 关键词: Affect; Behavior; Biological; Biological Models; Brain; Breast; Bypass; Cancer Biology; Cell Death; Cell Maintenance; Cell Survival; Cell physiology; Cells; Dermis; Development; Embryo; Embryonic Development; Evolution; FGF8 gene; Family; Family member; Fibroblast Growth Factor; Gene Expression; Genes; Genetic; Genets; Goals; Growth Factor Gene; Knock-out; Lead; Limb Development; Limb structure; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mouse Strains; Mus; Muscle; Nature; Pattern; Phenotype; Play; Process; Proteins; Role; Series; Signal Transduction; Source; Stem cells; Testicular Neoplasms; Testing; Tissues; gastrulation; insight; interest; lung development; malignant breast neoplasm; member; migration; mutant; nephrogenesis; respiratory smooth muscle; somitogenesis; spine bone structure; tumor

The long term goal of this project is to understand how a very important family of gene products, 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. FGFs, when dysregulated, are instrumental in various forms of cancer, and the particular FGFs we study play important roles in breast and prostate cancer. To achieve the project's long terms goals, we focus on the normal role FGFs play during mouse embryogenesis. Therefore our short term goals are to generate the necessary mouse strains that will allow us to control FGF gene expression during embryogenesis and to generate and test specific hypotheses concerning FGF action in the embryo. For example, we recently overturned a hypothesis which stated that FGF8 was required for the process of somitogenesis, the process by which much of the body's muscle, dermis and all vertebrae are generated (Development 132: 3859). This lead to a new hypothesis that the role of FGF8 in this embryonic process was redundant with one or more of the other five FGFs expressed in this region. This issue of redundancy has implications for the biology of cancer as more than one FGF can be acting in a given tumor. Fibroblast growth factors (FGFs) comprise a family of 22 members that govern a wide spectrum of cell biological behaviors such as proliferation, cell death, migration and gene expression. In FY 2009, as part of our general interest in FGF signaling, in collaborative studies we have defined the role of Fgf9 in airway smooth muscle differentiation in lung development (<I>Dev. Dyn.</I>, 2009 238:123). Another family member we have a long standing interest in is <I>Fgf8</I>, which plays an important role in the progression of both breast cancer and prostate cancer. To understand how such abnormal <I>Fgf8</I> expression affects cell function in cancer, our long-term goal is to determine the normal role of <I>Fgf8</I>, during vertebrate embryogenesis, using the mouse as a model system. <I>Fgf8</I> is expressed in a variety of regions of the embryo that may be termed "organizers": regions that are a source of signals that pattern and thus "organize" the surrounding tissue. Previously we have generated an allelic series generated at the <I>Fgf8</I> locus (Meyers et al. 1998 <I>Nature Genetics</I> 18:136), as well as Cre-mediated tissue-specific knockouts (Lewandoski et al. 2000 <I>Nature Genetics</I>, 26:460; Lewandoski 2001 <I>Nature Reviews Genet.</I> 2:743; Lewandoski 2007 <I>Handb Exp Pharmaco</I> 178: 235) and revealed a role for <I>Fgf8</I> in organizers that control gastrulation, limb, and brain development. We have produced a valuable mouse line (T-Cre) that expresses Cre specifically throughout all embryonic mesodermal lineages, thus allowing us to control gene expression in these lineages. This line is useful to bypass the embryonic lethal phenotypes of genes that affect early development, yet allows the study of the role of such genes throughout much of the embryo (Verheyden et al, 2005 <I>Development</I>, 132: 4235; Wahl et al, 2007 <I>Development</I>, 134; 4033; Dunty et al <I>Development</I>, 135:85; Aulehla, A. et al, 2008 <I>Nat Cell Biol.</I>, 10:186; MacDonald S.T. et al 2008 <I>Cardiovasc Res. </I>, 79: 448; Kumar A, et al, 2008 <I>Dev. Dyn.</I>, 237:5391; Tzchori et al, 2009 <I>Development</I>, 136; 1375) . Inactivation of <I>Fgf8</I> with TCre has revealed that <I>Fgf8</I> plays a central role in cell survival and gene expression during kidney development (Perantoni et al 2005, <I>Development</I>, 132: 3859). Another surprising insight emerging from these studies is that <I>Fgf8</I> is not required for several mesodermal signaling centers that control the process of somite formation, where it was thought to play a role. To investigate this, we are studying mutants in which <I>Fgf8</I> and each of the other five <I>Fgfs</I> expressed in these regions are simultaneously inactivated. Importantly, we have uncovered a redundant role between <I>Fgf4</I> and <I>Fgf8</I> in somite formation. This functional redundancy 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.

该项目的长期目标是了解一个非常重要的基因产品（称为成纤维细胞生长因子（FGF））如何控制广泛的细胞生物学行为，例如增殖，细胞死亡，迁移，干细胞维持和基因表达。 FGF在失调时，在各种形式的癌症中发挥了作用，并且我们研究的特定FGF在乳腺癌和前列腺癌中起着重要作用。为了实现项目的长期目标，我们专注于FGF在小鼠胚胎发生过程中发挥的正常作用。 因此，我们的短期目标是生成必要的小鼠菌株，这将使我们能够控制胚胎发生过程中FGF基因表达，并生成和测试有关胚胎中FGF作用的特定假设。例如，我们最近推翻了一个假设，该假设表明，fgf8是体温发生过程所必需的，这是产生人体肌肉，真皮和所有椎骨的过程（发育132：3859）。这导致了一个新的假设，即FGF8在该胚胎过程中的作用是多余的，而在该区域中表达的其他五个FGF中的一个或多个。这个冗余问题对癌症的生物学具有影响，因为一个以上的FGF可以在给定的肿瘤中作用。成纤维细胞生长因子（FGFS）组成了一个由22个成员组成的家族，该家族控制着广泛的细胞生物学行为，例如增殖，细胞死亡，迁移和基因表达。在2009财年，作为我们对FGF信号传导的普遍兴趣的一部分，在协作研究中，我们定义了FGF9在气道平滑肌分化在肺发育中的作用（<i>dev。dyn。dyn。dyn。</i>，2009 238：123）。另一个家庭成员我们对IS <i> fgf8 </i>有很长的兴趣，这在乳腺癌和前列腺癌的发展中起着重要作用。为了了解这种异常异常的表达如何影响癌症的细胞功能，我们的长期目标是在脊椎动物胚胎发生过程中使用小鼠作为模型系统来确定<i> fgf8 </i>的正常作用。 <i> fgf8 </i>在可能称为“组织者”的胚胎的多个区域表达：是模式的信号来源，从而“组织”周围组织的源。以前，我们已经生成了一个在<i> fgf8座位上生成的等位基因系列（Meyers等，1998年自然遗传学18：136），以及CRE介导的组织特异性敲除（Lewandoski等人（Lewandoski等，2000年，2000年自然遗传学） Genet。</i> 2：743；我们产生了一条有价值的小鼠系（T-CRE），该系列在所有胚胎中胚层谱系中都特别表达CRE，从而使我们能够控制这些谱系中的基因表达。这条线对于绕过影响早期发育的基因的胚胎致死表型很有用，但可以研究这种基因在整个胚胎中的作用（Verheyden等，2005 <i> development </i>，132：4235; A. et al，2008年，</i> </i>，10：186; 1375）。 与TCRE的<i> FGF8 <i> FGF8 </i>的灭活已经表明，<i> fgf8 <i> fgf8 </i>在肾脏发育过程中在细胞存活和基因表达中起着核心作用（Perantoni等，2005，<i> evelacmence </i>，132：3859）。这些研究中出现的另一个令人惊讶的见解是，几个中胚层信号传导中心不需要<i> fgf8 </i>，这些中心信号传导中心控制着体征形成过程，在这些过程中认为它起了作用。为了调查这一点，我们正在研究其中的突变体，其中<i> fgf8 </i>以及在这些区域中表达的其他五个fgfs </i>同时灭活。重要的是，我们已经发现了Somite组中<i> fgf4 </i>和<i> fgf8 </i>之间的冗余作用。由于发现两个FGF在睾丸肿瘤中异常活跃，因此这种功能冗余对癌症具有影响。此外，这种冗余对进化具有影响，因为同一FGF在肢体发育中起着补偿性作用。