Genetic insights into the mechanisms of Fgf signaling

Brewer, J. Richard; Mazot, Pierre; Soriano, Philippe

doi:10.1101/gad.277137.115

Cited by 197 publications

(208 citation statements)

References 254 publications

(348 reference statements)

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“…Conversely, it is possible that HSPG co-receptors may facilitate Fgf4 engagement of receptors expressed in PrE, as previous studies have demonstrated that HSPGs are essential for promoting paracrine signaling (Cai et al, 2014; Shimokawa et al, 2011). Second, as Fgf signaling is known to engage a number of signaling pathways in addition to Erk (Brewer et al, 2016), it is also possible that the signaling pathways engaged by Fgfr1 or Fgfr2 are different, or vary between the Epi and the PrE precursor cells. It is also possible that the duration of signaling varies in different cell types, promoting cell differentiation (Brewer et al, 2016; Marshall, 1995; Vasudevan et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Second, as Fgf signaling is known to engage a number of signaling pathways in addition to Erk (Brewer et al, 2016), it is also possible that the signaling pathways engaged by Fgfr1 or Fgfr2 are different, or vary between the Epi and the PrE precursor cells. It is also possible that the duration of signaling varies in different cell types, promoting cell differentiation (Brewer et al, 2016; Marshall, 1995; Vasudevan et al, 2015). Although Erk1/2 is a prominent pathway engaged by Fgf signaling (Brewer et al, 2016; Brewer et al, 2015; Lanner and Rossant, 2010), how Fgf signaling regulates PrE specification genes through Erk and other pathways remains incompletely understood, and assessing signaling mechanisms in PrE formation and in the exit from pluripotency will require further studies.…”

Section: Discussionmentioning

confidence: 99%

“…The Fgf family includes 18 ligands and four Fgf receptors (Fgfr1, Fgfr2, Fgfr3 and Fgfr4) that are expressed in many tissues and play pleiotropic roles during embryonic and postnatal development, and in adult tissue maintenance (Brewer et al, 2016; Ornitz and Itoh, 2015). Both Fgfr1 and Fgfr2 have been implicated in the preimplantation embryo, but it is unclear which receptor(s) Fgf4 engages during PrE development.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency

et al. 2017

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SUMMARY Activation of the Fgf signaling pathway during preimplantation development of the mouse embryo is known to be essential for differentiation of the inner cell mass and the formation of the primitive endoderm (PrE). We now show using fluorescent reporter knock-in lines that Fgfr1 is expressed in all cell populations of the blastocyst, while Fgfr2 expression becomes restricted to extraembryonic lineages, including the PrE. We further show that loss of both receptors prevents the development of the PrE and demonstrate that Fgfr1 plays a more prominent role in this process than Fgfr2. Last, we document an essential role for Fgfrs in ES cell differentiation, with again Fgfr1 having a larger influence than Fgfr2 in ES cell exit from the pluripotent state. Collectively, these results identify mechanisms through which Fgf signaling regulates inner cell mass (ICM) lineage restriction and cell commitment during preimplantation development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency

et al. 2017

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“…FGFR signaling activates at least four downstream intracellular signaling pathways including, MAPK, PI3K/AKT, PLCγ, and STATs (reviewed in Ornitz and Itoh, 2015; Brewer et al, 2016). In the growth plate, FGFR3 activates STAT1 and the ERK1/2 and p38 branches of the MAPK pathway (Figure 2) (Su et al, 1997; Chen et al, 1999; Li et al, 1999; Chen et al, 2001; Legeai-Mallet et al, 2004; Raucci et al, 2004; de Frutos et al, 2007; Parafioriti et al, 2009).…”

Section: Fgfr3 Signaling In the Growth Platementioning

confidence: 99%

Achondroplasia: Development, pathogenesis, and therapy

Ornitz

Legeai-Mallet

2017

Developmental Dynamics

182

177

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Autosomal dominant mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) cause Achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include Hypochondroplasia (Hch), Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN), and Thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions.

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“…Abnormal FGF signaling is linked to many congenital disorders as well as cancers (Beenken and Mohammadi, 2009; Brewer et al, 2016; Turner and Grose, 2010). Understanding the fundamental basis of FGF signaling is the key to uncover mechanisms of development and diseases.…”

Section: Introductionmentioning

confidence: 99%

Unique patterns of organization and migration of FGF-expressing cells during Drosophila morphogenesis

Zhou

Patel

et al. 2017

Developmental Biology

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Fibroblast growth factors (FGF) are essential signaling proteins that regulate diverse cellular functions in developmental and metabolic processes. In Drosophila, the FGF homolog, branchless (bnl) is expressed in a dynamic and spatiotemporally restricted pattern to induce branching morphogenesis of the trachea, which expresses the Bnl-receptor, breathless (btl). Here we have developed a new strategy to determine bnl-expressing cells and study their interactions with the btl-expressing cells in the range of tissue patterning during Drosophila development. To enable targeted gene expression specifically in the bnl expressing cells, a new LexA based bnl enhancer trap line was generated using CRISPR/Cas9 based genome editing. Analyses of the spatiotemporal expression of the reporter in various embryonic stages, larval or adult tissues and in metabolic hypoxia, confirmed its target specificity and versatility. With this tool, new bnl expressing cells, their unique organization and functional interactions with the btl-expressing cells were uncovered in a larval tracheoblast niche in the leg imaginal discs, in larval photoreceptors of the developing retina, and in the embryonic central nervous system. The targeted expression system also facilitated live imaging of simultaneously labeled Bnl sources and tracheal cells, which revealed a unique morphogenetic movement of the embryonic bnl- source. Migration of bnl- expressing cells may create a dynamic spatiotemporal pattern of the signal source necessary for the directional growth of the tracheal branch. The genetic tool and the comprehensive profile of expression, organization, and activity of various types of bnl-expressing cells described in this study provided us with an important foundation for future research investigating the mechanisms underlying Bnl signaling in tissue morphogenesis.

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Genetic insights into the mechanisms of Fgf signaling

Cited by 197 publications

References 254 publications

Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency

Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency

Achondroplasia: Development, pathogenesis, and therapy

Unique patterns of organization and migration of FGF-expressing cells during Drosophila morphogenesis

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