FGF receptors 1 and 2 are key regulators of keratinocyte migration <i>in vitro</i> and in wounded skin

Meyer, Michaël; Müller, Anna Katharina; Yang, Jingxuan; Moik, Daniel; Ponzio, Gilles; Ornitz, David M.; Grose, Richard; Werner, Sabine

doi:10.1242/jcs.108167

Cited by 95 publications

(83 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…FGFR1 and FGFR2 have similar in vitro signaling potency and ligand response profiles to FGF9 and FGF18 (Zhang et al, 2006), ligands that have key roles in regulating skeletal development (Hung et al, 2016Liu et al, 2007Liu et al, , 2002Ohbayashi et al, 2002). In several tissues, including the limb bud, palate, lung, kidney, liver, cerebellum, epidermis and inner ear, Fgfr1 and Fgfr2 show significant functional redundancy (Böhm et al, 2010;Huh et al, 2015;Meyer et al, 2012;Ornitz and Itoh, 2015;Poladia et al, 2006;SimsLucas et al, 2011;Smith et al, 2012;White et al, 2006;Yang et al, 2010;Yu et al, 2015;Yu and Ornitz, 2008). To study the roles of FGFR signaling in the osteoprogenitor lineage, the Osx-GFP::Cre (Osx-Cre) allele was crossed to floxed alleles of Fgfr1 and Fgfr2 (Rodda and McMahon, 2006;Trokovic et al, 2003;Yu et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Karuppaiah

Lim

et al. 2016

Development

Self Cite

View full text Add to dashboard Cite

Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cellautonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.

show abstract

Section: Resultsmentioning

confidence: 99%

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Karuppaiah

Lim

et al. 2016

Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…The contribution of FGF signaling in response to tissue injury is well established; however, most studies have focused on the role of EC and stromal FGF signaling in tissue repair (31,(45)(46)(47). Whether the vascular response to injury in vivo requires a direct FGF signal remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Oladipupo

Smith

Santeford

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

118

107

View full text Add to dashboard Cite

Endothelial cells (ECs) express fibroblast growth factor receptors (FGFRs) and are exquisitely sensitive to FGF signals. However, whether the EC or another vascular cell type requires FGF signaling during development, homeostasis, and response to injury is not known. Here, we show that Flk1-Cre or Tie2-Cre mediated deletion of FGFR1 and FGFR2 (Fgfr1/2Flk1-Cre or Fgfr1/ 2 Tie2-Cre mice), which results in deletion in endothelial and hematopoietic cells, is compatible with normal embryonic development. As adults, Fgfr1/2 Flk1-Cre mice maintain normal blood pressure and vascular reactivity and integrity under homeostatic conditions. However, neovascularization after skin or eye injury was significantly impaired in both Fgfr1/2Flk1-Cre and Fgfr1/2Tie2-Cre mice, independent of either hematopoietic cell loss of FGFR1/2 or vascular endothelial growth factor receptor 2 (Vegfr2) haploinsufficiency. Also, impaired neovascularization was associated with delayed cutaneous wound healing. These findings reveal a key requirement for cell-autonomous EC FGFR signaling in injuryinduced angiogenesis, but not for vascular homeostasis, identifying the EC FGFR signaling pathway as a target for diseases associated with aberrant vascular proliferation, such as age-related macular degeneration, and for modulating wound healing without the potential toxicity associated with direct manipulation of systemic FGF or VEGF activity.choroidal neovascularization | oxygen-induced retinopathy | retinopathy of prematurity | neoangiogenesis N eovascularization is critical for tissue repair and pathological conditions, including aberrant ocular angiogenesis and cancer (1-4). Although FGF signaling has been prominently implicated in these processes based on genetic inactivation experiments in mice and in vitro studies, the functional in vivo requirement of this pathway in the endothelial cell (EC) vs. other vascular cell types is not known (5-8).The FGF family is composed of 18 signaling ligands, which interact with four cell surface tyrosine kinase receptors. FGF receptor (FGFR) signaling regulates many biological processes, including survival, differentiation, proliferation, and angiogenesis through the activation of RAS-RAF-MAPK, PI3K, STAT, and PLC gamma pathways (6, 9). The EC response to FGF signals is well described in in vitro models of angiogenesis (10, 11). Moreover, previous gene expression analysis showed that Fgfr1 and Fgfr2 were the predominant Fgfrs in ECs (5), whereas Fgfr3 was sparsely detected (12, 13) and Fgfr4 expression was not reported (8). To this end, and given the critical role of FGFRs 1 and 2 during embryonic development, we tested the hypothesis that EC FGFR1/2 may play a key role during vascular development, homeostasis, and response to injury.Studies aimed at understanding the functional requirement of vascular FGF signaling have demonstrated a critical role in homeostasis and angiogenesis (14-16). In these studies, in vivo expression of an adenoviral-based soluble FGF trap (sFGFR) or a dominant inhibitor of all FGFRs (FGF...

show abstract

“…Flow Cytometry-Flow cytometry measurements were performed as described previously (34). Briefly, cells were trypsinized and stained with primary antibodies for 10 -30 min on ice, washed, and stained with secondary antibody for 10 -30 min on ice.…”

Section: Methodsmentioning

confidence: 99%

Mutations in the Paxillin-binding Site of Integrin-linked Kinase (ILK) Destabilize the Pseudokinase Domain and Cause Embryonic Lethality in Mice

Moik

Böttcher

Махина

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Integrin-linked kinase is believed to be recruited to focal adhesions (FAs) by binding paxillin via a conserved motif in the pseudokinase domain. Results: The paxillin-binding motif is not required for FA localization but for ILK stability, parvin and paxillin binding, and mouse development. Conclusion: ILK does not require paxillin for FA localization. Significance: Reducing ILK stability perturbs cell migration and development.

show abstract

FGF receptors 1 and 2 are key regulators of keratinocyte migration in vitro and in wounded skin

Cited by 95 publications

References 45 publications

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Mutations in the Paxillin-binding Site of Integrin-linked Kinase (ILK) Destabilize the Pseudokinase Domain and Cause Embryonic Lethality in Mice

Contact Info

Product

Resources

About