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Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.

Pancreatic cancer has one of the highest mortalities among all malignancies and there is an urgent need for new therapy. This might be achieved by resolving the detailed biological mechanism, and in this study we examined how pancreatic cancer cells develop aggressive properties by focusing on signalling through the fibroblast growth factor (FGF)10 and FGF receptor (FGFR)2, which play important roles in pancreatic organogenesis. Immunostaining of pancreatic cancer tissues showed that FGFR2 was expressed in cancer cells, whereas FGF10 was expressed in stromal cells surrounding the cancer cells. Patients with high FGFR2 expression in cancer cells had a shorter survival time compared to those with low FGFR2 expression. Fibroblast growth factor 10 induced cell migration and invasion of CFPAC-1 and AsPC-1 pancreatic cancer cells through interaction with FGFR2-IIIb, a specific isoform of FGFR2. Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)- β 1, and increased secretion of TGF- β 1 protein from these cell lines. These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis. This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

We have previously demonstrated that tooth size is determined by dental mesenchymal factors. Exogenous bone morphogenetic protein (BMP)4, Noggin, fibroblast growth factor (FGF)3 and FGF10 have no effect on tooth size, despite the expressions of Bmp2, Bmp4, Fgf3, Fgf10 and Lef1 in the dental mesenchyme. Among the wingless (Wnt) genes that are differentially expressed during tooth development, only Wnt5a is expressed in the dental mesenchyme. The aims of the present study were to clarify the expression pattern of Wnt5a in developing tooth germs and the role of Wnt5a in the regulation of tooth size by treatment with exogenous WNT5A with/without an apoptosis inhibitor on in vitro tooth germs combined with transplantation into kidney capsules. Wnt5a was intensely expressed in both the dental epithelium and mesenchyme during embryonic days 14–17, overlapping partly with the expressions of both Shh and Bmp4. Moreover, WNT5A retarded the development of tooth germs by markedly inducing cell death in the non-dental epithelium and mesenchyme but not widely in the dental region, where the epithelial–mesenchymal gene interactions among Wnt5a, Fgf10, Bmp4 and Shh might partly rescue the cells from death in the WNT5A-treated tooth germ. Together, these results indicate that WNT5A-induced cell death inhibited the overall development of the tooth germ, resulting in smaller teeth with blunter cusps after tooth-germ transplantation. Thus, it is suggested that Wnt5a is involved in regulating cell death in non-dental regions, while in the dental region it acts as a regulator of other genes that rescue tooth germs from cell death.

Sorcin, a key calcium-sensing protein, regulates calcium concentration within the endoplasmic reticulum (ER), promoting apoptosis resistance and ER stress. It also modulates downstream signaling pathways of the epidermal growth factor receptor (EGFR), influencing cellular migration and invasion in non-small-cell lung carcinoma (NSCLC) cell lines. For this purpose, this study investigates the relationship between Sorcin and EGFR expression during lung development at the physiological level. Our study was conducted on WT and Sorcin Knock-out ( Sri −/− ) mice, where we performed various analyses, including histological examination, gene and protein expression analysis, and confocal microscopy. Our findings reveal that Sri −/− mice, compared to wild-type controls, exhibit: (1) impaired alveolarization and abnormal development of bronchi and bronchioles, as observed in histological sections; (2) decreased expression of genes encoding branching morphogenesis markers (e.g., Fgf10 ) and surfactant proteins (e.g., Sp-b , Sp-c and Abca3 ), as shown by real-time PCR; (3) increased glycogen content decreased lipid droplets, indicative of type II pneumocyte immaturity and impaired surfactant lipid production; (4) reduced levels of EGFR, RAS and RAB5C proteins, consistent with defects in lung maturation and surfactant protein recycling, as demonstrated by Western blot analysis; and (5) increased expression of phalloidin, α-smooth muscle actin and vimentin, suggesting increased bronchial thickening associated with airway tissue remodeling. Collectively, these data reveal a novel role for Sorcin in lung alveolarization, pulmonary surfactant production, and airway remodeling associated with bronchial contractility, supporting its involvement in respiratory diseases such as respiratory distress syndrome (RDS), asthma and chronic obstructive pulmonary disease (COPD).

Meis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1 / 2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10 , a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis. Double conditional knockout of Meis1/2 in the limb forming region of mouse embryos results in the complete absence of limb, while embryos developed with one functional Meis allele, so identifying the role of Meis in antero-posterior and proximo-distal patterning.

Folding of the mammalian cerebral cortex into sulcal fissures and gyral peaks is the result of complex processes that are incompletely understood. Previously we showed that genetic deletion of Flrt1/3 adhesion molecules causes folding of the smooth mouse cortex into sulci resulting from increased lateral dispersion and faster neuron migration, without progenitor expansion. Here, we show in mice that combining the Flrt1/3 double knockout with an additional genetic deletion that causes progenitor expansion, greatly enhances cortex folding. Expansion of intermediate progenitors by deletion of Cep83 leads to a relative increase in Flrt-mutant neurons resulting in enhanced formation of sulci. Expansion of apical progenitors by deletion of Fgf10 leads to a relative reduction in Flrt-mutant neurons resulting in enhanced formation of gyri. These results together with computational modeling identify key developmental mechanisms, such as adhesive properties, cell densities and migration of cortical neurons, that cooperate to promote cortical gyrification. The complex processes guiding mammalian cortical folding are incompletely understood. Here authors report that cortical folding was enhanced in mice by combining mutations affecting neuron adhesion and progenitor expansion, producing both sulci and gyri.

Background Temporal lobe epilepsy (TLE) is frequently associated with cognitive impairments, such as memory deficits, attention disorders, and executive dysfunction. Given that these cognitive deficits are closely linked to neuronal loss in TLE, fibroblast growth factor 10 (FGF10), a molecule recognized for its neuroprotective properties, has emerged as a promising therapeutic candidate. The kainic acid (KA)-induced epilepsy model can replicate key pathological features of TLE. The study aims to investigate the potential role of FGF10 in TLE, using the KA-induced model as an experimental framework. Methods We induced epilepsy in mice using KA and administered intranasal FGF10 over 14 days or delivered an AAV virus to overexpress FGF10. Seizure activity was monitored via video-electroencephalography (EEG), and behavioral tests were conducted to assess spatial cognition, anxiety-related behaviors, and depressive-like behaviors. Neuronal damage was evaluated using Nissl staining and TUNEL staining. To explore the molecular mechanisms underlying FGF10’s effects, we performed RNA sequencing, followed by validation with Western blotting and qRT-PCR. Additionally, we generated FGFR2 conditional knockout (cKO) mice to investigate the role of FGF10-FGFR2 signaling. Results FGF10 treatment significantly reduced seizure frequency and improved epilepsy-related cognitive deficits. It also exerted neuroprotective effects, as evidenced by reduced neuronal death in KA-induced epileptic mice. RNA sequencing revealed decreased CALB1 levels in the hippocampal dentate gyrus of epileptic mice, which were restored following FGF10 administration. Crucially, the therapeutic benefits of FGF10 were abolished in FGFR2-cKO mice, indicating that FGFR2 is essential for FGF10’s effects. Conclusions Our findings demonstrate that FGF10 alleviates seizures and cognitive dysfunction in epilepsy, likely through FGFR2-dependent mechanisms involving CALB1 modulation. These results highlight FGF10 as a potential therapeutic target for epilepsy, offering a novel strategy for improving treatment outcomes in patients with TLE.

The penile tubular urethra forms by canalization of the urethral plate without forming an obvious urethral groove in mice, while the urethral epithelium forms a fully open urethral groove before urethra closure through the distal-opening-proximal-closing process in humans and guinea pigs. Our knowledge of the mechanism of penile development is mainly based on studies in mice. To reveal how the fully opened urethral groove forms in humans and guinea pigs, we compared the expression patterns and levels of key developmental genes using in situ hybridization and quantitative PCR during glans and preputial development between guinea pigs and mice. Our results revealed that, compared with mouse preputial development, which started before sexual differentiation, preputial development in guinea pigs was delayed and initiated at the same time that sexual differentiation began. Fgf10 was mainly expressed in the urethral epithelium in developing genital tubercle (GT) of guinea pigs. The relative expression of Shh, Fgf8, Fgf10, Fgfr2, and Hoxd13 was reduced more than 4-fold in the GT of guinea pigs compared to that of mice. Hedgehog and Fgf inhibitors induced urethral groove formation and restrained preputial development in cultured mouse GT, while Shh and Fgf10 proteins induced preputial development in cultured guinea pig GT. Our discovery suggests that the differential expression of Shh and Fgf10/Fgfr2 may be the main reason a fully opened urethral groove forms in guinea pigs, and it may be similar in humans as well.

Background The epithelial-mesenchymal signaling involving SHH-FOXF1, TBX4-FGF10, and TBX2 pathways is an essential transcriptional network operating during early lung organogenesis. However, precise regulatory interactions between different genes and proteins in this pathway are incompletely understood. Methods To identify TBX2 and TBX4 genome-wide binding sites, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) in human fetal lung fibroblasts IMR-90. Results We identified 14,322 and 1,862 sites strongly-enriched for binding of TBX2 and TBX4, respectively, 43.95% and 18.79% of which are located in the gene promoter regions. Gene Ontology, pathway enrichment, and DNA binding motif analyses revealed a number of overrepresented cues and transcription factor binding motifs relevant for lung branching that can be transcriptionally regulated by TBX2 and/or TBX4. In addition, TBX2 and TBX4 binding sites were found enriched around and within FOXF1 and its antisense long noncoding RNA FENDRR, indicating that the TBX4-FGF10 cascade may directly interact with the SHH-FOXF1 signaling. Conclusions We highlight the complexity of transcriptional network driven by TBX2 and TBX4 and show that disruption of this crosstalk during morphogenesis can play a substantial role in etiology of lung developmental disorders.

The molecular mechanisms for epithelial differentiation have been studied by observing skin development in embryogenesis, but the early signaling modulations involved in tongue epithelial differentiation are not completely understood. Based on the gene expression patterns of the Fgf signaling molecules and previous results from Fgf10 and Fgfr2b knockout mice, it was hypothesized that there would be fundamental signaling interactions through the epithelial Fgfr2b and its mesenchymal ligand Fgf10 to regulate tongue epithelium differentiation. To elucidate these reciprocal interactions in tongue epithelial differentiation, this study employed an in vitro tongue organ culture system with antisense-oligodeoxynucleotides (AS-ODNs) and recombinant protein-soaked bead implantation for the loss-of-function and gain-of-function studies. Functional analysis of Fgf signaling revealed precise reciprocal interactions, which showed that mesenchymal Fgf10 rather than Fgf7 modulates tongue epithelial differentiation via Fgfr2b in a temporal- and spatial-specific manner.