Regulation of FGF10 Signaling in Development and Disease

Abstract

Fibroblast Growth Factor 10 (FGF10) is a multifunctional mesenchymal-epithelial signaling growth factor, which is essential for multi-organ development and tissue homeostasis in adults. Furthermore, FGF10 deregulation has been associated with human genetic disorders and certain forms of cancer. Upon binding to FGF receptors with heparan sulfate as co-factor, FGF10 activates several intracellular signaling cascades, resulting in cell proliferation, differentiation, and invasion. FGF10 activity is modulated not only by heparan sulfate proteoglycans in the extracellular matrix, but also by hormones and other soluble factors. Despite more than 20 years of research on FGF10 functions, context-dependent regulation of FGF10 signaling specificity remains poorly understood. Emerging modes of FGF10 signaling regulation will be described, focusing on the role of FGF10 trafficking and sub-cellular localization, heparan sulfate proteoglycans, and miRNAs. Systems biology approaches based on quantitative proteomics will be considered for globally investigating FGF10 signaling specificity. Finally, current gaps in our understanding of FGF10 functions, such as the relative contribution of receptor isoforms to signaling activation, will be discussed in the context of genetic disorders and tumorigenesis.

Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity

“…Perturbation of these mechanisms during prenatal development can result in complete or partial inhibition of lung morphogenesis . Therefore, we suggest that variants in the CTNNB1 and TBX4 genes, crucial members of Wnt and FGF signaling, could act synergistically to produce a distinct phenotype observed in our patient, resulting in respiratory failure during the neonatal period. Our findings expand the mutational burden of the previously proposed genetic model of lethal lung diseases, in which both rare non‐coding single nucleotide variants (SNVs) and heterozygous TBX4 or FGF10 SNVs or deletion CNVs, as well as double heterozygous TBX4 and TBX5 variants, contribute to the lung phenotype and suggest epistatic interactions of genes from the same signaling pathway …”

“…Beta‐catenin, encoded by CTNNB1 (MIM#116806) and T‐box transcription factor 4, encoded by TBX4 (MIM#601719) are crucial proteins in canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling, respectively …”

MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10

“…Fibroblast growth factor 10 (FGF10) has been found in all examined vertebrates, and it is a multifunctional mesenchymalepithelial signaling growth factor that is essential for multiorgan development and tissue homeostasis in adults (21,22). FGF10, a member of the family of fibroblast growth factors (FGFs), was generated from a common ancestral gene during the early evolution of vertebrates and retains similar amino acid sequences and biochemical functions (23).…”

Role of Fibroblast Growth Factor 10 in Mesenchymal Cell Differentiation During Lung Development and Disease

“…It is very likely that other players such as heparan sulfate proteoglycans, which have a high affinity for Fgf10 as well as other growth factors, are interacting with Fgf10 to restrict its activity distally in order to control the branching process. For details on Fgf10 signaling per se , we refer to other mini-reviews also published as part of this special issue ( Ndlovu et al, 2018 ; Watson and Francavilla, 2018 ). During the subsequent stages of mouse development (canalicular: E16.5 to E17.5, saccular: E17.5 to postanatal day (P) 5; alveolar: P5 to P28), Fgf10 is still significantly expressed suggesting that Fgf10 could play multiple roles beyond the pseudoglandular stage not only in the epithelium, but also directly or indirectly in the mesenchyme.…”