Initiation to end point: the multiple roles of fibroblast growth factors in neural development

Mason, Ivor

doi:10.1038/nrn2189

Cited by 265 publications

(259 citation statements)

References 165 publications

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“…The etiology of these deficits remains enigmatic to date. Precise regulation of BMP, Wnt, and Ras/ERK signaling is crucial to normal brain development (39)(40)(41)(42), raising the possibility that genotype might influence neurocognitive outcome, as appears to be the case for congenital heart disease (22,23). The results provide a means of stratifying non-syndromic patients to assess the extent to which specific genotypes contribute to neurocognitive outcome.…”

Section: Discussionmentioning

confidence: 99%

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

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

100

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Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10 −11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

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Section: Discussionmentioning

confidence: 99%

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

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

100

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“…FGFRs are activated via 22 different FGF ligands resulting in downstream FRS2 and extracellular signal-regulated kinase (ERK) phosphorylation ( 13 ); their signaling is modulated endogenously by multiple negative intrinsic feedback loops (15)(16)(17). Furthermore, alternative splicing of FGF receptors mediates different responses to FGF ligands in epithelial (expressing IIIb splice variants) and mesenchymal tissues (expressing IIIc splice variants) in development ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

“…The FGFR family consists of four receptor tyrosine kinases, which are common targets of deregulation by translocation, point mutation, and amplifi cation in cancer (12)(13)(14). FGFRs are activated via 22 different FGF ligands resulting in downstream FRS2 and extracellular signal-regulated kinase (ERK) phosphorylation ( 13 ); their signaling is modulated endogenously by multiple negative intrinsic feedback loops (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

et al. 2014

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The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplifi ed in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplifi ed tumors are also sensitive to fi broblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifi cations, the 8p12 region included multiple centers of amplifi cation, suggesting marked genomic heterogeneity. FGFR1 -amplifi ed tumor cells were dependent on FGFR ligands in vitro and in vivo . Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1 -amplifi ed tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplifi ed and MYC-overexpressing tumors may benefi t from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1 -amplifi ed lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE:Amplifi cation of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1 , thus providing clinical hypotheses for refi nement of patient selection. Cancer Discov; 4(2);

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“…FGFR1 has been implicated in neural induction, patterning, survival, proliferation, and differentiation, and more recently, in axon pathfinding and synapse formation (41). FGFR1 was recognized by Ptpro and Ptprb as a substrate.…”

Section: Discussionmentioning

confidence: 99%

Substrate Specificity of R3 Receptor-like Protein-tyrosine Phosphatase Subfamily toward Receptor Protein-tyrosine Kinases

Sakuraba

Shintani

Tani

et al. 2013

Journal of Biological Chemistry

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Background: Our understanding of the physiological relevance between receptor-like protein-tyrosine phosphatase (RPTP) and receptor protein-tyrosine kinase (RPTK) is limited. Results: Multiple RPTKs were identified as substrates for the R3 RPTP subfamily. Conclusion: Members of the R3 subfamily show a similar but distinct specificity toward RPTKs. Significance: This study sheds light on physiological roles of the R3 RPTP subfamily.

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Initiation to end point: the multiple roles of fibroblast growth factors in neural development

Cited by 265 publications

References 165 publications

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Substrate Specificity of R3 Receptor-like Protein-tyrosine Phosphatase Subfamily toward Receptor Protein-tyrosine Kinases

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