FGF signaling regulates development by processes beyond canonical pathways

Ray, Ayan; Mazot, Pierre; Brewer, J. Richard; Catela, Catarina; Dinsmore, Colin J.; Soriano, Philippe

doi:10.1101/gad.342956.120

Cited by 23 publications

(60 citation statements)

References 76 publications

(126 reference statements)

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“…The question of whether canonical FGFR signaling pathways are required to mediate cell adhesion was addressed by comparing FGFR null mutants, FGFR mutants that uncouple activation of all major downstream signaling pathways, and mutants in which the tyrosine kinase domain is inactivated. Interestingly, the effects of FGF‐induced cell–matrix or cell–cell interactions were lost in the FGFR null mutants and in the kinase‐dead mutants, but were retained in mutants that lacked connections to the canonical downstream signaling pathways (Ray et al, 2020). These data suggest that FGF–FGFR signaling regulates cell adhesion through kinase‐dependent mechanisms that are distinct from the classical downstream signaling pathways.…”

Section: Regulation Of Fgfr Signal Transduction By Extracellular and ...mentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

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Section: Regulation Of Fgfr Signal Transduction By Extracellular and ...mentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

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“…Investigation of the downstream targets of FGFR2 activation confirmed our assessment that the effects of the Fgfr2c C342Y mutation are cell type specific. ERK1/2 is the main effector of FGF signaling ( Brewer et al, 2016 ; Ray et al, 2020 ). ERK pathway promotes osteoblast differentiation and bone formation in vitro and in vivo ( Xiao et al, 2000 ; Xiao et al, 2002 ; Kim et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Meckel’s Cartilage in Mandibular Development and Dysmorphogenesis

et al. 2022

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The Fgfr2cC342Y/+ Crouzon syndrome mouse model carries a cysteine to tyrosine substitution at amino acid position 342 (Cys342Tyr; C342Y) in the fibroblast growth factor receptor 2 (Fgfr2) gene equivalent to a FGFR2 mutation commonly associated with Crouzon and Pfeiffer syndromes in humans. The Fgfr2c C342Y mutation results in constitutive activation of the receptor and is associated with upregulation of osteogenic differentiation. Fgfr2cC342Y/+ Crouzon syndrome mice show premature closure of the coronal suture and other craniofacial anomalies including malocclusion of teeth, most likely due to abnormal craniofacial form. Malformation of the mandible can precipitate a plethora of complications including disrupting development of the upper jaw and palate, impediment of the airway, and alteration of occlusion necessary for proper mastication. The current paradigm of mandibular development assumes that Meckel’s cartilage (MC) serves as a support or model for mandibular bone formation and as a template for the later forming mandible. If valid, this implies a functional relationship between MC and the forming mandible, so mandibular dysmorphogenesis might be discerned in MC affecting the relationship between MC and mandibular bone. Here we investigate the relationship of MC to mandible development from the early mineralization of the mandible (E13.5) through the initiation of MC degradation at E17.7 using Fgfr2cC342Y/+ Crouzon syndrome embryos and their unaffected littermates (Fgfr2c+/+). Differences between genotypes in both MC and mandibular bone are subtle, however MC of Fgfr2cC342Y/+ embryos is generally longer relative to unaffected littermates at E15.5 with specific aspects remaining relatively large at E17.5. In contrast, mandibular bone is smaller overall in Fgfr2cC342Y/+ embryos relative to their unaffected littermates at E15.5 with the posterior aspect remaining relatively small at E17.5. At a cellular level, differences are identified between genotypes early (E13.5) followed by reduced proliferation in MC (E15.5) and in the forming mandible (E17.5) in Fgfr2cC342Y/+ embryos. Activation of the ERK pathways is reduced in the perichondrium of MC in Fgfr2cC342Y/+ embryos and increased in bone related cells at E15.5. These data reveal that the Fgfr2c C342Y mutation differentially affects cells by type, location, and developmental age indicating a complex set of changes in the cells that make up the lower jaw.

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“…Another candidate for regulation by FGF-signaling is BIM. Deletion of one Bim allele, which encodes an apoptosis initiator that directly activates BAK/BAX [36, 37], will partially rescue aberrant cell death that underlie craniofacial defects that are due to the loss of Fgfr1 and Fgfr2 [29]. Our model for genetically rescuing cell death in the Fgf8 mutant kidney presents a future opportunity to explore the role of FGFs in pro-survival signaling in vivo .…”

Section: Discussionmentioning

confidence: 99%

Fgf8 promotes survival of nephron progenitors by regulating BAX/BAK-mediated apoptosis

Anderson

Misaghian

Sharma

et al. 2022

Preprint

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Fibroblast growth factors (Fgfs) have long been implicated in processes critical to embryonic development, such as cell survival, migration, and differentiation. Several mouse models of organ development ascribe a prosurvival requirement specifically to FGF8. Here, we explore the potential role of prosurvival FGF8 signaling in kidney development. We have previously demonstrated that conditional deletion of Fgf8 in the mesodermal progenitors that give rise to the kidney leads to renal aplasia in the mutant neonate. Deleterious consequences caused by loss of FGF8 begin to manifest by E14.5 when massive aberrant cell death occurs in the cortical nephrogenic zone in the rudimentary kidney as well as in the renal vesicles that give rise to the nephrons. To rescue cell death in the Fgf8 mutant kidney, we inactivate the genes encoding the pro-apoptotic factors BAK and BAX. In a wild-type background, the loss of Bak and Bax abrogates normal cell death and has minimal effect on renal development. However, in Fgf8 mutants, the combined loss of Bak and Bax rescues aberrant cell death in the kidneys and restores some measure of kidney development: 1) the nephron progenitor population is greatly increased; 2) some glomeruli form, which are rarely observed in Fgf8 mutants; and 3) kidney size is rescued by about 50% at E18.5. The development of functional nephrons, however, is not rescued. Thus, FGF8 signaling is required for nephron progenitor survival by regulating BAK / BAX and for subsequent steps involving, as yet, undefined roles in kidney development.

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FGF signaling regulates development by processes beyond canonical pathways

Cited by 23 publications

References 76 publications

New developments in the biology of fibroblast growth factors

New developments in the biology of fibroblast growth factors

Meckel’s Cartilage in Mandibular Development and Dysmorphogenesis

Fgf8 promotes survival of nephron progenitors by regulating BAX/BAK-mediated apoptosis

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