成纤维细胞生长因子研究进展

成纤维细胞生长因子8(fibroblast growth factor 8,FGF8)是成纤维细胞生长因子家族的成员之一,是动物组织器官发育过程中重要的分泌性调控因子.在胚胎发育的早期,FGF8广泛表达.它可以介导胚胎期的上皮和间充质的转化,在原肠的形成,早期器官如前后脑、咽、心脏、生殖器官和指等的形成和分化中都起到关键性的作用.本文就FGF8在器官发育中的作用及其研究进行概述.     

成纤维细胞生长因子17研究进展

成纤维细胞生长因子17(FGF17)是成纤维细胞生长因子(FGF)家族的成员之一,并与FGF8、FGF18组成FGF8亚家族。在胚胎时期FGF17扮演重要角色,对多种组织器官起着重要作用。研究发现,FGF17不仅参与了脑部发育和神经形成,而且参与骨骼、动脉的发育和肿瘤等生物过程。现针对FGF17的特点,及其在胚胎发育、神经系统、癌症等方面的作用进行综述。     

FGF10:胚胎器官发育中重要的多功能信号分子

从诱导脊椎动物早期胚胎的中胚层到器官和组织的形成,成纤维细胞生长因子家族(FGFs)在其各个阶段起着重要的作用。FGFs在各种器官形成中担负上皮间质相互作用的重要调控因子,特别是FGF10,无论在外胚层上皮还是在内皮层上皮都是重要的间质调控因子。如果离开该因子,胚胎组织器官发生将无法完成。就FGF10调控四肢、支气管-肺脏、胰腺、脑垂体、皮肤、牙齿、下颌下腺和白色脂肪等组织器官形态发生的最新研究进展进行综述。     

成纤维细胞生长因子8(FGF8)研究进展

成纤维细胞生长因子8(fibroblast growth factor 8,FGF8)是成纤维细胞生长因子(FGFs)家族的成员之一。其在人胚胎时期多种组织内进行表达,对各种器官的形成中起着重要的作用。在正常成人体内,FGF8的表达水平受到严格的限制,然而在某些癌细胞或炎症部位中大量表达,特别是在激素类癌症的发生和发展中起着重要的作用。因此应用FGF8抗体治疗激素类癌症,为临床提供了新的治疗途径。     

FGF-1及其突变体的研究进展

酸性成纤维细胞生长因子(acid fibroblastgrowth factor,FGF-1)是成纤维细胞生长因子家族重要的成员之一。来源于三个胚层的细胞都能够表达FGF-1,其生物学效应非常广泛,在组织和器官发育、血管发生、血细胞生成、肿瘤发生和伤口愈合等方面发挥着重要作用。FGF-1不但可以在细胞外通过胞内信号通路而且也可以进入细胞内部发挥生物学功能。主要综述FGF-1信号转导方面的研究进展、促细胞增殖作用的可能分子机制以及将来的临床应用前景。     

FGF9与FGFR3受体在骨发育与疾病中的作用

成纤维细胞生长因子9(fibroblast growth factor,FGF9)最初发现于人类神经胶质瘤细胞,是成纤维细胞生长因子家族的成员之一.研究发现FGF9在多种组织的发育及疾病的发生中起重要作用.FGF9与肝素结合活化FGFR3受体,可作用于软骨细胞,在骨骼发育及损伤过程中抑制软骨细胞增生和软骨内骨化.FGF9基因缺失或突变可分别导致骨骼发育不良或肿瘤.本文简要综述FGF9与FGFR3受体在骨发育中的作用及其致病机制的研究进展.     

人FGF-1对免疫系统的影响

酸性成纤维细胞生长因子 (acidfibroblastgrowthfactor,aFGF或FGF-1 )是成纤维细胞生长因子家族成员之一 ,是一种重要的生长因子。人FGF 1 (FGF-1 )是一个 1 7～ 1 8kDa的非糖基化多肽 ,三胚层来源的细胞都可以表达。FGF-1的生物学效应非常广泛 ,在组织和器官发育、血管发生、血细胞生成、肿瘤发生、伤口愈合等方面发挥重要的作用。FGF-1对人体的免疫系统也有重要的影响 ,能提高多种刺激诱导的T细胞增殖、凋亡及细胞因子的产生。主要概述了FGF-1的生物学效应、对免疫系统的影响及其潜在的临床应用价值。     

FGF信号通路在内耳发育调控和毛细胞再生中的作用

内耳是感受听觉和平衡觉的复杂器官。在内耳发育过程中,成纤维生长因子(fibroblast growth factor, FGF)信号通路参与了听基板的诱导、螺旋神经节(statoacoustic ganglion, SAG)的发育以及Corti器感觉上皮的分化。FGF信号开启了内耳早期发育的基因调控网络,诱导前基板区域以及听基板的形成。正常表达的FGF信号分子可促进听囊腹侧成神经细胞的特化,但成熟SAG神经元释放的过量FGF5可抑制此过程,形成负反馈环路使SAG在稳定状态下发育。FGF20在Notch信号通路的调控下参与了前感觉上皮区域向毛细胞和支持细胞的分化过程,而内毛细胞分泌的FGF8可调控局部支持细胞分化为柱细胞。人类FGF信号通路异常可导致多种耳聋相关遗传病。此外,FGF信号通路在低等脊椎动物毛细胞自发再生以及干细胞向内耳毛细胞诱导过程中都起到了关键作用。本文综述了FGF信号通路在内耳发育调控以及毛细胞再生中的作用及其相关研究进展,以期为毛细胞再生中FGF信号通路调控机制的阐明奠定理论基础。     

角质细胞生长因子研究进展

角质细胞生长因子（KGF）属于成纤维细胞生长因子家族,它通过与受体（KGFR）的结合,特异性地刺激上皮细胞的增殖.KGF基因表达受到正负调控作用,正负调控作用的平衡对于KGF正常发挥功能具有重要意义.KGF具有多种生物学功能：参与组织、器官的发育,具有损伤防治功能,与癌症的发生有着密切的联系.     

成纤维细胞生长因子的生理病理作用及应用进展

成纤维细胞生长因子(fibroblast growth factors,FGFs)以旁分泌或内分泌的方式参与多种生理活动的调节,维护成体组织的正常结构、功能并参与代谢调控。FGFs通过结合配体硫酸乙酰肝素或klotho使成纤维细胞生长因子受体二聚化而发挥生物学作用。过去的十年中,FGFs结构和分子机制的研究成果改变了人们对FGF信号在人类健康和疾病发生、发展中的认识,为以FGF及其受体为靶点的药物开发带来新的突破。文章综述了FGF的生理、病理作用及最新应用研究进展。     

FGF8 spliceforms mediate early mesoderm and posterior neural tissue formation in Xenopus

The relative contributions of different FGF ligands and spliceforms to mesodermal and neural patterning in Xenopus have not been determined, and alternative splicing, though common, is a relatively unexplored area in development. We present evidence that FGF8 performs a dual role in X. laevis and X. tropicalis early development. There are two FGF8 spliceforms, FGF8a and FGF8b, which have very different activities. FGF8b is a potent mesoderm inducer, while FGF8a has little effect on the development of mesoderm. When mammalian FGF8 spliceforms are analyzed in X. laevis, the contrast in activity is conserved. Using a loss-of-function approach, we demonstrate that FGF8 is necessary for proper gastrulation and formation of mesoderm and that FGF8b is the predominant FGF8 spliceform involved in early mesoderm development in Xenopus. Furthermore, FGF8 signaling is necessary for proper posterior neural formation; loss of either FGF8a or a reduction in both FGF8a and FGF8b causes a reduction in the hindbrain and spinal cord domains.     

FGF8 Activates Proliferation and Migration in Mouse Post-Natal Oligodendrocyte Progenitor Cells

Fibroblast growth factor 8 (FGF8) is a key molecular signal that is necessary for early embryonic development of the central nervous system, quickly disappearing past this point. It is known to be one of the primary morphogenetic signals required for cell fate and survival processes in structures such as the cerebellum, telencephalic and isthmic organizers, while its absence causes severe abnormalities in the nervous system and the embryo usually dies in early stages of development. In this work, we have observed a new possible therapeutic role for this factor in demyelinating disorders, such as leukodystrophy or multiple sclerosis. In vitro, oligodendrocyte progenitor cells were cultured with differentiating medium and in the presence of FGF8. Differentiation and proliferation studies were performed by immunocytochemistry and PCR. Also, migration studies were performed in matrigel cultures, where oligodendrocyte progenitor cells were placed at a certain distance of a FGF8-soaked heparin bead. The results showed that both migration and proliferation was induced by FGF8. Furthermore, a similar effect was observed in an in vivo demyelinating mouse model, where oligodendrocyte progenitor cells were observed migrating towards the FGF8-soaked heparin beads where they were grafted. In conclusion, the results shown here demonstrate that FGF8 is a novel factor to induce oligodendrocyte progenitor cell activation, migration and proliferation in vitro, which can be extrapolated in vivo in demyelinated animal models.     

FGF17b and FGF18 have different midbrain regulatory properties from FGF8b or activated FGF receptors

Early patterning of the vertebrate midbrain and cerebellum is regulated by a mid/hindbrain organizer that produces three fibroblast growth factors (FGF8, FGF17 and FGF18). The mechanism by which each FGF contributes to patterning the midbrain, and induces a cerebellum in rhombomere 1 (r1) is not clear. We and others have found that FGF8b can transform the midbrain into a cerebellum fate, whereas FGF8a can promote midbrain development. In this study we used a chick electroporation assay and in vitro mouse brain explant experiments to compare the activity of FGF17b and FGF18 to FGF8a and FGF8b. First, FGF8b is the only protein that can induce the r1 gene Gbx2 and strongly activate the pathway inhibitors Spry1/2, as well as repress the midbrain gene Otx2. Consistent with previous studies that indicated high level FGF signaling is required to induce these gene expression changes, electroporation of activated FGFRs produce similar gene expression changes to FGF8b. Second, FGF8b extends the organizer along the junction between the induced Gbx2 domain and the remaining Otx2 region in the midbrain, correlating with cerebellum development. By contrast, FGF17b and FGF18 mimic FGF8a by causing expansion of the midbrain and upregulating midbrain gene expression. This result is consistent with Fgf17 and Fgf18 being expressed in the midbrain and not just in r1 as Fgf8 is. Third, analysis of gene expression in mouse brain explants with beads soaked in FGF8b or FGF17b showed that the distinct activities of FGF17b and FGF8b are not due to differences in the amount of FGF17b protein produced in vivo. Finally, brain explants were used to define a positive feedback loop involving FGF8b mediated upregulation of Fgf18, and two negative feedback loops that include repression of Fgfr2/3 and direct induction of Spry1/2. As Fgf17 and Fgf18 are co-expressed with Fgf8 in many tissues, our studies have broad implications for how these FGFs differentially control development.     

Cardiac arterial pole alignment is sensitive to FGF8 signaling in the pharynx

Morphogenesis of the cardiac arterial pole is dependent on addition of myocardium and smooth muscle from the secondary heart field and septation by cardiac neural crest cells. Cardiac neural crest ablation results in persistent truncus arteriosus and failure of addition of myocardium from the secondary heart field leading to malalignment of the arterial pole with the ventricles. Previously, we have shown that elevated FGF signaling after neural crest ablation causes depressed Ca2+ transients in the primary heart tube. We hypothesized that neural crest ablation results in elevated FGF8 signaling in the caudal pharynx that disrupts secondary heart field development. In this study, we show that FGF8 signaling is elevated in the caudal pharynx after cardiac neural crest ablation. In addition, treatment of cardiac neural crest-ablated embryos with FGF8b blocking antibody or an FGF receptor blocker rescues secondary heart field myocardial development in a time- and dose-dependent manner. Interestingly, reduction of FGF8 signaling in normal embryos disrupts myocardial secondary heart field development, resulting in arterial pole malalignment. These results indicate that the secondary heart field myocardium is particularly sensitive to FGF8 signaling for normal conotruncal development, and further, that cardiac neural crest cells modulate FGF8 signaling in the caudal pharynx.     

Transgenic expression of FGF8 and FGF10 induces transdifferentiation of pancreatic islet cells into hepatocytes and exocrine cells

FGF signaling is essential for normal development of pancreatic islets. To examine the effects of overexpressed FGF8 and FGF10 on pancreatic development, we generated FGF8- and FGF10-transgenic mice (Tg mice) under the control of the glucagon promoter. In FGF8-Tg mice, hepatocyte-like cells were observed in the periphery of pancreatic islets, but areas of alpha and beta cells did not decrease, whereas in FGF10-Tg mice, pancreatic ductal and acinar cells were found in islets, concomitantly with disturbed beta-cell differentiation. These results suggest that FGF8 and FGF10 play important roles in development of hepatocytes and exocrine cells, respectively, and explain the absence of FGF8 expression in normal islets and pancreatic hypoplasia in FGF10-deficient mice.     

Beta-catenin-dependent Wnt signaling in apical ectodermal ridge induction and FGF8 expression in normal and limbless mutant chick limbs

The fibroblast growth factor (FGF) and beta-catenin-dependent Wnt signaling pathways are key regulators of vertebrate limb development. FGF10 induces expression of Wnt3a, which regulates the formation and FGF8 expression of the apical ectodermal ridge (AER). In amelic limbless limbs, an AER fails to form and FGF8 is not expressed, despite expression of FGF10. It has been found that Wnt3a is initially expressed in limbless ectoderm, although subsequently is drastically reduced. In addition, changes in the expression pattern or level of several Frizzled receptors, Axin, Lef1/Tcf1 and beta-catenin have been found in limbless limbs. Notably, while normal wing buds respond to LiCl-stimulated activation of beta-catenin-dependent signaling by forming ectopic, FGF8-expressing AER, LiCl was unable to induce an AER in limbless wing buds. The results of this study suggest that the limbless gene is required for beta-catenin-dependent Wnt signaling in limb ectoderm leading to FGF8 expression and AER formation.     

Role of fibroblast growth factor 8 in growth and progression of hormonal cancer

Hormonal cancers such as breast and prostate cancer arise from steroid hormone-regulated tissues. In addition to breast and prostate cancer hormonal regulation has also a role in endometrial, ovarian, testis and thyroid carcinomas. The effects of estrogens, androgens and progestagens on tumor growth are largely mediated by paracrine and autocrine target molecules which include growth factors and growth factor receptors. During cancer progression the hormonal growth regulation is often lost or overcome by an inappropriate activation of growth factor signaling cascades. One of the growth factors which have been associated with the regulation of growth and progression of hormonal cancer is fibroblast growth factor 8 (FGF8) which has also been recognized as an oncogene. FGF8 is widely expressed during embryonic development. It has been shown to mediate embryonic epithelial-mesenchymal transition and to have a crucial role in gastrulation and early organization and differentiation of midbrain/hindbrain, pharyngeal, cardiac, urogenital and limb structures. During adulthood FGF8 expression is much more restricted but in hormonal cancers it becomes frequently activated. High level of FGF8 expression in tumors is associated with a poor prognosis at least in prostate cancer. In experimental models FGF8 induces and facilitates prostate tumorigenesis and increases growth and angiogenesis of tumors. Several lines of evidence for autocrine and paracrine loops in the growth regulation of breast, prostate and ovarian cancer by FGF8 have been suggested.     

FGF8 dose-dependent regulation of embryonic submandibular salivary gland morphogenesis

FGF8 has been shown to play important morphoregulatory roles during embryonic development. The observation that craniofacial, cardiovascular, pharyngeal, and neural phenotypes vary with Fgf8 gene dosage suggests that FGF8 signaling induces differences in downstream responses in a dose-dependent manner. In this study, we investigated if FGF8 plays a dose-dependent regulatory role during embryonic submandibular salivary gland (SMG) morphogenesis. We evaluated SMG phenotypes of Fgf8 hypomorphic mice, which have decreased Fgf8 gene function throughout embryogenesis. We also evaluated SMG phenotypes of Fgf8 conditional mutants in which Fgf8 function has been completely ablated in its expression domain in the first pharyngeal arch ectoderm from the time of arch formation. Fgf8 hypomorphs have hypoplastic SMGs, whereas conditional mutant SMGs exhibit ontogenic arrest followed by involution and are absent by E18.5. SMG aplasia in Fgf8 ectoderm conditional mutants indicates that FGF8 signaling is essential for the morphogenesis and survival of Pseudoglandular Stage and older SMGs. Equally important, the presence of an initial SMG bud in Fgf8 conditional mutants indicates that initial bud formation is FGF8 independent. Mice heterozygous for either the Fgf8 null allele (Fgf8(+/N)) or the hypomorphic allele (Fgf8(+/H)) have SMGs that are indistinguishable from wild-type (Fgf8(+/+)) mice which suggest that there is not only an FGF8 dose-dependent phenotypic response, but a nonlinear, threshold-like, epistatic response as well. We also found that enhanced FGF8 signaling induced, and abrogated FGF8 signaling decreased, SMG branching morphogenesis in vitro. Furthermore, since FGF10 and Shh expression is modulated by Fgf8 levels, we postulated that exogenous FGF10, Shh, or FGF10 + Shh peptide supplementation in vitro would largely "rescue" the abnormal SMG phenotype associated with decreased FGF8 signaling. This is as expected, though there is no synergistic effect with FGF10 + Shh peptide supplementation. These in vitro experiments model the principle that mutations have different effects in the context of different epigenotypes.