Fibroblast Growth Factor 6.

Fibroblast Growth Factor 6 (FGF6), also referred to as HST2 or HBGF6, is a member of the Fibroblast Growth Factor (FGF), the Heparin Binding Growth Factor (HBGF) and the Heparin Binding Secretory Transforming Gene (HST) families. The genomic and protein structure of FGF6 is highly conserved among varied species, as is its expression in muscle and muscle progenitor cells. Like other members of the FGF family, FGF6 regulates cell proliferation, differentiation, and migration. Specifically, it plays key roles in myogenesis and muscular regeneration, angiogenesis, along with iron transport and lipid metabolism. Similar to others from the FGF family, FGF6 also possesses oncogenic transforming activity, and as such is implicated in a variety of cancers.

Fibroblast Growth Factor 6 Promotes Adipocyte Progenitor Cell Proliferation for Adipose Tissue Homeostasis.

The de novo differentiation of hyperplastic adipocytes from adipocyte progenitor cells (APCs) is accompanied by a reduction in adipose tissue fibrosis and inflammation and improvement in insulin sensitivity in obesity and aging. However, the regulators of APC proliferation are poorly understood. Here, we show that fibroblast growth factor 6 (FGF6) acts in an autocrine and/or paracrine manner to control platelet-derived growth factor receptor α-positive APC proliferation via extracellular signal-regulated kinase (ERK) signaling. Specific FGF6 overexpression in inguinal white adipose tissue (iWAT) improved the signs of high-fat diet- or aging-induced adipose hypertrophy and insulin resistance. Conversely, chronic FGF6 expression blockade in iWAT, mediated by a neutralizing antibody or Fgf6 expression deficiency, impaired adipose tissue expansion and glucose tolerance. Overall, our data suggest that FGF6 acts as a proliferative factor for APCs to maintain fat homeostasis and insulin sensitivity.

FGF6 promotes cardiac repair after myocardial infarction by inhibiting the Hippo pathway.

OBJECTIVES: Myocardial infarction (MI) commonly occurs in patients with coronary artery disease and have high mortality. Current clinical strategies for MI still limited to reducing the death of myocardial cells but failed to replace these cells. This study aimed to investigate the role of fibroblast growth factor 6 (FGF6) in enhancing the proliferative potential of cardiomyocytes (CMs) after ischemic injury via the Hippo pathway. MATERIALS AND METHODS: Expression of FGF6 protein was analysed in mice with MI induced by ligation of the left anterior descending coronary artery. Activation of the Hippo pathway and the proliferation potential were examined in ischemic CMs, treated with FGF6 protein or transfected with an adeno-virus carrying FGF6 sh-RNA. Immunofluorescence staining and western blotting were performed to assess the relationship between FGF6 and the Hippo pathway. RESULTS: We found that FGF6 expression was significantly increased in the MI mouse model. Knockdown of FGF6 synthesis resulted in poorer heart function after MI. By contrast, treatment with recombinant human FGF6 protein improved heart function, reduced infarct size, and promoted cardiac repair. Additionally, FGF6 restrains the activation of the Hippo pathway and subsequently promotes nuclear accumulation of YAP. This was largely counteracted by treatment with extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126. CONCLUSION: FGF6 inhibits the Hippo pathway via ERK1/2, and facilitates nuclear translocation of YAP, and thereby promotes cardiac repair after MI.

Fibroblast growth factor 6 regulates sizing of the muscle stem cell pool.

Skeletal muscle stem cells, i.e., satellite cells (SCs), are the essential source of new myonuclei for skeletal muscle regeneration following injury or chronic degenerative myopathies. Both SC number and regenerative capacity diminish during aging. However, molecular regulators that govern sizing of the initial SC pool are unknown. We demonstrate that fibroblast growth factor 6 (FGF6) is critical for SC pool scaling. Mice lacking FGF6 have reduced SCs of early postnatal origin and impaired regeneration. By contrast, increasing FGF6 during the early postnatal period is sufficient for SC expansion. Together, these data support that FGF6 is necessary and sufficient to modulate SC numbers during a critical postnatal period to establish the quiescent adult muscle stem cell pool. Our work highlights postnatal development as a time window receptive for scaling a somatic stem cell population via growth factor signaling, which might be relevant for designing new biomedical strategies to enhance tissue regeneration.

LINC00265 promotes the viability, proliferation, and migration of bladder cancer cells via the miR-4677-3p/FGF6 axis.

BACKGROUND: Bladder cancer (BCa) is a common genitourinary malignancy with higher incidence in males. Long intergenic non-protein coding RNA 265 (LINC00265) is identified as an oncogene in many malignancies, while its role in BCa development remains unknown. PURPOSE: To explore the functions and mechanism of LINC00265 in BCa. RESEARCH DESIGN: Reverse transcription quantitative polymerase chain reaction was performed to examine LINC00265 expression in BCa cells. Cell counting kit-8 assays, colony formation assays, TdT-mediated dUTP Nick-End Labeling assays, and Transwell assays were conducted to examine BCa cell viability, proliferation, apoptosis, and migration. Luciferase reporter assays and RNA immunoprecipitation assays were carried out to explore the binding capacity between miR-4677-3p and messenger RNA fibroblast growth factor 6 (FGF6) (or LINC00265). Xenograft tumor model was established to explore the role of LINC00265 in vivo. RESULTS: LINC00265 was highly expressed in BCa cells. LINC00265 knockdown inhibited xenograft tumor growth and BCa cell viability, proliferation and migration while enhancing cell apoptosis. Moreover, LINC00265 interacted with miR-4677-3p to upregulate the expression of FGF6. FGF6 overexpression reversed the suppressive effect of LINC00265 knockdown on malignant phenotypes of BCa cells. CONCLUSIONS: LINC00265 promotes the viability, proliferation, and migration of BCa cells by binding with miR-4677-3p to upregulate FGF6 expression.

Skeletal muscle-targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance.

Obesity, a major health care issue, is characterized by metabolic abnormalities in multiple tissues, including the skeletal muscle. Although dysregulation of skeletal muscle metabolism can strongly influence the homeostasis of systemic energy, the underlying mechanism remains unclear. We found promoter hypermethylation and decreased gene expression of fibroblast growth factor 6 (FGF6) in the skeletal muscle of individuals with obesity using high-throughput sequencing. Reduced binding of the cyclic AMP responsive element binding protein-1 (CREB1) to the hypermethylated cyclic AMP response element, which is a regulatory element upstream of the transcription initiation site, partially contributed to the downregulation of FGF6 in patients with obesity. Overexpression of Fgf6 in mouse skeletal muscle stimulated protein synthesis, activating the mammalian target of rapamycin pathway, and prevented the increase in weight and the development of insulin resistance in high-fat diet-fed mice. Thus, our findings highlight the role played by Fgf6 in regulating skeletal muscle hypertrophy and whole-body metabolism, indicating its potential in strategies aimed at preventing and treating metabolic diseases.

FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis.

Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.

FGF6 enhances muscle regeneration after nerve injury by relying on ERK1/2 mechanism.

BACKGROUND: Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS: In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS: FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION: These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.

Characterization and expression analysis of FGF6 (fibroblast growth factor 6) genes of grass carp (Ctenopharyngodon idellus) reveal their regulation on muscle growth.

The present study was conducted to investigate the regulative function of FGF6 in the muscle growth of grass carp (Ctenopharyngodon idellus) by the bioinformatics analysis and expression pattern analyses of FGF6 genes in different developmental stages and tissues, as well as the correlation analysis between muscle growth and FGF6 expression after fish were fed with different levels of dietary lotus leaf flavonoids (LLF) (0, 0.03%, 0.06%, 0.09%). Results showed that the FGF6a and FGF6b genes are two homologs of the FGF6 family, encoding 205 and 209 amino acids, respectively. Alignment of amino acid sequences and phylogenetic analysis demonstrated that FGF6a and FGF6b are highly conserved with other vertebrates. Quantitative RT-PCR analysis showed both FGF6a and FGF6b expressions were high in brain and muscle but low in other examined tissues. During embryonic development, FGF6a and FGF6b mRNA expressions could be detected as early as at fertilized egg stage and displayed the highest value at cleavage stage. Dietary LLF affected the gene expression of FGF6 in white muscle. The relative expression of FGF6a of 0.06% LLF group was significantly higher than that of 0.09% LLF group, while FGF6b expression of 0.06% LLF group was higher than those of other groups (P < 0.05). The muscle fiber diameter was significantly higher in 0.06% LLF group in comparison with other groups, while the fiber density in this group was lower (P < 0.05). Both FGF6a and FGF6b expressions were positively correlated with fiber diameter but negatively correlated with fiber density. These results collectively suggest that FGF6a and FGF6b play an important role in muscle growth regulation in grass carp.

A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene.

Standard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor-encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6 variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism.

Vascular calcification and growth arrest specific protein 6 levels in chronic renal failure / Calcificación vascular y detención de crecimiento de proteína específica 6 niveles en insuficiencia renal crónica

INTRODUCTION: Cardiovascular disease is the main cause of mortality and morbidity in chronic renal failure. It's known that vascular calcification (VC) and carotid intima media thickness (CIMT) are strongly associated with cardiovascular diseases. Growth arrest specific protein 6 (Gas6) is a vitamin K-dependent protein and regulates various processes such as proliferation, cell survival, migration and inflammation. Gas6 is known to protect endothelial cells and vascular smooth muscle cells against apoptosis by inhibiting Bcl-2 induced Caspase 3 activation. The relationship between Gas6 and cardiovascular diseases has been demonstrated in many mouse models and cell cultures. However, there are conflicting reports whether Gas6 levels are increasing or decreasing in human studies of diabetic and/or chronic renal failure. In present study the aim was to examine plasma Gas6 levels and its relation with CIMT and coronary artery calcification score (CACS) in chronic kidney disease (CKD) patients. METHODS: Total of 137 patients of which 32 chronic hemodialysis and 105 predialysis patients as well as 73 healthy controls were enrolled in the study. Human Gas6 levels in serum samples were studied by ELISA method. CIMT was measured by ultrasonography. CACS was measured by multislice computed tomography. RESULTS: The mean age was 54.37±16.61 years in dialysis group, 55.20±14.80 years in predialysis group and 53.26±9.04 years in control group. Serum creatinine was 0.78±0.16 mg/dl in the control group and 1.96±1.64 mg/dl in the predialysis group and 5.94±1.55 mg/dl in the dialysis group. 24 hours urine protein levels were significally higher in the dialysis group than the predialysis and the control group. CIMT values were similar in predialysis and dialysis groups. These values were significantly higher than the control group. Although CACS was higher in dialysis group than predialysis and control group, the results were not statistically significant since the distribution range was very wide. Gas6 was 98.84±53.32 ng/mL in the control group and statistically higher than the dialysis (63.85±38.92 ng/mL) and the predialysis groups (54.96±38.49 ng/mL) (p=0.001). Gas6 levels were lower in diabetic patients than non-diabetics (53.69±35.26 ng/mL, 69.26±47.50 ng/mL, p=0.023, respectively). Negative correlation was detected between Gas6 and age, BMI, CACS, carotid IMT and proteinuria. In the logistic regression analysis, Gas6 remained significantly associated with BMI, CIMT and proteinuria. CONCLUSION: In our study, a negative correlation of Gas6 with BMI, CACS, CIMT and proteinuria and lower Gas6 levels in diabetic patients support that decreased Gas6 levels in chronic renal failure may have a role in vascular calcification through altered glucose tolerance, chronic inflammation, endothelial dysfunction and increased apoptosis. Our study has an importance because it is the first study showing a relation between Gas6 and proteinuria, CACS and carotid IMT in patients with chronic renal failure

INTRODUCCIÓN: La enfermedad cardiovascular es la principal causa de mortalidad y morbilidad en la insuficiencia renal crónica. Se sabe que la calcificación vascular (CV) y el grosor de la íntima-media de la carótida (CIMT, por sus siglas en inglés) están vinculados de forma muy estrecha con enfermedades cardiovasculares. La proteína específica del gen 6 de la detención de crecimiento (Gas6) es una proteína dependiente de la vitamina K y regula diversos procesos, como la proliferación, la supervivencia celular, la migración y la inflamación. La proteína Gas6 es conocida por proteger las células endoteliales y las células musculares lisas vasculares contra la apoptosis mediante la inhibición de la activación de la caspasa-3 inducida por la proteína Bcl-2. Se ha demostrado la relación entre la Gas6 y las enfermedades cardiovasculares en muchos modelos de ratones y cultivos celulares. Sin embargo, existen informes contradictorios acerca de si los niveles de Gas6 aumentan o disminuyen en estudios de humanos con insuficiencia renal crónica y/o diabética. En este estudio, el objetivo fue examinar los niveles plasmáticos de Gas6 y su relación con el CIMT y la puntuación de calcificación de las arterias coronarias (CACS, por sus siglas en inglés) en pacientes con enfermedad renal crónica (ERC). MATERIAL Y MÉTODOS: Un total de 137 pacientes fueron incluidos en el estudio, de los cuales 32 estaban en hemodiálisis crónica, 105 en prediálisis, y 73 pacientes representaban controles sanos. Se esudiaron los niveles de Gas6 en muestras de suero mediante el método ELISA. El CIMT se midió por medio de ecografía. La CACS se midió mediante tomografía computarizada multicorte. RESULTADOS: La edad media fue de 54,37 ± 16,61 años en el grupo de diálisis; 55,20 ± 14,80 años en el grupo de prediálisis, y 53,26 ± 9,04 años en el grupo de control. La creatinina sérica fue de 0,78 ± 0,16 mg/dl en el grupo de control; 1,96 ± 1,64 mg/dl en el de prediálisis, y 5,94 ± 1,55 mg/dl en el de diálisis. Las concentraciones de proteína en orina de 24 horas fueron significativamente más altas en el grupo de diálisis que en los de prediálisis y control. Los valores del CIMT fueron similares en los grupos de prediálisis y de diálisis. Estos valores fueron considerablemnete más altos que en el grupo de control. Aunque la CACS fue más alta en el grupo de diálisis que en los otros dos, los resultados no fueron estadísticamente significativos, ya que el rango de distribución fue muy amplio. La proteína Gas6 fue de 98,84 ± 53,32 ng/ml en el grupo de control y estadísticamente más alta que en los grupos de diálisis (63,85 ± 38,92 ng/ml) y de prediálisis (54,96 ± 38,49 ng/ml) (p = 0,001). Los niveles de Gas6 fueron más bajos en los pacientes diabéticos que en los no diabéticos (53,69 ± 35,26 ng/ml; 69,26 ± 47,50 ng/ml, [p = 0,023], respectivamente). Se detectó una correlación negativa entre la proteína Gas6 y la edad, el IMC, la CACS, el CIMT y la proteinuria. En el análisis de regresión logística, la Gas6 se mantuvo estrechamente relacionada con el IMC, el CIMT y la proteinuria. CONCLUSIÓN: En nuestro estudio, la correlación negativa de Gas6 con IMC, CACS, CIMT y proteinuria, y los niveles más bajos de Gas6 en pacientes diabéticos sustentan la idea de que la disminución de los niveles de Gas6 en la insuficiencia renal crónica puede jugar un papel en la calcificación vascular a través de la tolerancia alterada a la glucosa, la inflamación crónica, la disfunción endotelial y el aumento de la apoptosis. La importancia de nuestro estudio radica en que es el primero que muestra una relación entre la Gas6 y la proteinuria, la CACS y el CIMT en pacientes con insuficiencia renal crónica

Total substitution of dietary fish oil by vegetable oils stimulates muscle hypertrophic growth in Senegalese sole and the upregulation of fgf6.

The long term effects of fish oil (FO) substitution by increasing the levels of vegetable oils (VO), 0% (CTR), 50% (VO50) and 100% (VO100), in diets for Senegalese sole were evaluated in terms of skeletal muscle cellularity and expression of related genes. After 140 days of feeding, all fish had similar body weight and length. The inclusion of 50% VO did not result in differences in muscle cellularity, but dorsal muscle cross-sectional area and fast-twitch fibre diameter increased in fish fed total FO substitution, whilst fibre density was reduced (P < 0.05) in relation to CTR. The total number of fibres was similar in all treatments. FO substitution did not affect the transcript levels of myogenic genes (myf5, mrf4, myog, myod1, myod2), but resulted in a two-fold increase of fgf6 transcript levels compared to CTR (P < 0.05). The relative expression of igf-I was higher in VO100 than in VO50, but was similar to CTR. FO substitution resulted in cellularity changes related to the stimulation of muscle hypertrophic growth, but not hyperplastic growth, and associated with a nutritional modulation of fgf6 by dietary VO. This study indicates that 50% VO does not affect the muscle phenotype, but total FO substitution stimulates muscle hypertrophy.

Different wound healing properties of dermis, adipose, and gingiva mesenchymal stromal cells.

Oral wounds heal faster and with better scar quality than skin wounds. Deep skin wounds where adipose tissue is exposed, have a greater risk of forming hypertrophic scars. Differences in wound healing and final scar quality might be related to differences in mesenchymal stromal cells (MSC) and their ability to respond to intrinsic (autocrine) and extrinsic signals, such as human salivary histatin, epidermal growth factor, and transforming growth factor beta1. Dermis-, adipose-, and gingiva-derived MSC were compared for their regenerative potential with regards to proliferation, migration, and matrix contraction. Proliferation was assessed by cell counting and migration using a scratch wound assay. Matrix contraction and alpha smooth muscle actin was assessed in MSC populated collagen gels, and also in skin and gingival full thickness tissue engineered equivalents (reconstructed epithelium on MSC populated matrix). Compared to skin-derived MSC, gingiva MSC showed greater proliferation and migration capacity, and less matrix contraction in full thickness tissue equivalents, which may partly explain the superior oral wound healing. Epidermal keratinocytes were required for enhanced adipose MSC matrix contraction and alpha smooth muscle actin expression, and may therefore contribute to adverse scarring in deep cutaneous wounds. Histatin enhanced migration without influencing proliferation or matrix contraction in all three MSC, indicating that salivary peptides may have a beneficial effect on wound closure in general. Transforming growth factor beta1 enhanced contraction and alpha smooth muscle actin expression in all three MSC types when incorporated into collagen gels. Understanding the mechanisms responsible for the superior oral wound healing will aid us to develop advanced strategies for optimal skin regeneration, wound healing and scar formation.

ALK5-mediated transforming growth factor ß signaling in neural crest cells controls craniofacial muscle development via tissue-tissue interactions.

The development of the craniofacial muscles requires reciprocal interactions with surrounding craniofacial tissues that originate from cranial neural crest cells (CNCCs). However, the molecular mechanism involved in the tissue-tissue interactions between CNCCs and muscle progenitors during craniofacial muscle development is largely unknown. In the current study, we address how CNCCs regulate the development of the tongue and other craniofacial muscles using Wnt1-Cre; Alk5(fl/fl) mice, in which loss of Alk5 in CNCCs results in severely disrupted muscle formation. We found that Bmp4 is responsible for reduced proliferation of the myogenic progenitor cells in Wnt1-Cre; Alk5(fl/fl) mice during early myogenesis. In addition, Fgf4 and Fgf6 ligands were reduced in Wnt1-Cre; Alk5(fl/fl) mice and are critical for differentiation of the myogenic cells. Addition of Bmp4 or Fgf ligands rescues the proliferation and differentiation defects in the craniofacial muscles of Alk5 mutant mice in vitro. Taken together, our results indicate that CNCCs play critical roles in controlling craniofacial myogenic proliferation and differentiation through tissue-tissue interactions.

The changes of muscle FGF-6 expression at different time points after exercise-induced muscle damage / Cambios de expresión de FGF-6 muscular en diferentes puntos del tiempo después del daño muscular inducido por ejercicio

OBJECTIVE: To investigate the changes of fibroblast growth factor (FGF)-6 expression in the regeneration and repair process after exercise-induced muscle damage (EIMD) and the relationship with skeletal muscle regeneration and repair. METHODS: The expression of FGF-6 at different time points was examined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry staining after a downhill treadmill exercise. Skeletal muscle injury and regeneration at different times after EIMD was assessed by haematoxylin and eosin (H & E) staining. RESULTS: The FGF-6 protein expression was initially elevated, followed by a gradual reduction, while the changes of FGF-6 mRNA were almost all raised after the treadmill exercise. CONCLUSION: The results point out that FGF-6 is closely related to skeletal muscle regeneration and repair, probably implying a dual function in muscle regeneration.

OBJETIVO: Investigar los cambios de expresión del factor de crecimiento fibroblástico (FGF)-6 en el proceso de regeneración y reparación después de daño muscular inducido por el ejercicio (DMIE) y la relación con la reparación y regeneración del músculo esquelético. MÉTODOS: La expresión de FGF-6 en diferentes tiempos fue examinada mediante reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR) y tinción inmunohistoquímica, después de un ejercicio de carrera descendente en cinta rodante. La lesión del músculo esquelético y la regeneración en diferentes momentos después del DMIE, fueron evaluadas mediante hematoxilina y eosina (H & E). RESULTADOS: La expresión de la proteína FGF-6 fue elevada al principio, seguida por una reducción gradual, mientras que los cambios de FGF-6 mRNA fueron casi todos incrementados tras los ejercicios en la cinta rodante. CONCLUSIÓN: Nuestros resultados señalan que FGF-6 se relaciona estrechamente con la regeneración del músculo esquelético, lo que probablemente implica una función dual en la regeneración muscular.

Preaxial polydactyly of the upper limb viewed as a spectrum of severity of embryonic events.

Preaxial polydactyly (PPD) is a common congenital abnormality and its classification varies among geneticists and hand surgeons. For example, the triphalangeal thumb, preaxial polysyndactyly, and the mirror hand deformity are considered as forms of PPD only in the genetics literature. Preaxial polydactyly is an error in the anteroposterior axis of the development of the upper limb. In this paper, the development of this axis is detailed and all molecular events that are known to lead to PPD are reviewed. Finally, based on the review, PPD is viewed as a spectrum of severity of embryonic events.

Cloning and expression analysis of Fgf5, 6 and 7 during early chick development.

FGFs with similar sequences can play different roles depending on the model organisms examined. Determining these roles requires knowledge of spatio-temporal Fgf gene expression patterns. In this study, we report the cloning of chick Fgf5, 6 and 7, and examine their gene expression patterns by whole mount in situ hybridization. We show that Fgf5's spatio-temporally restricted expression pattern indicates a potentially novel role during inner ear development. Fgf6 and Fgf7, although belonging to different subfamilies with diverged sequences, are expressed in similar patterns within the mesoderm. Alignment of protein sequences and phylogenetic analysis demonstrate that FGF5 and FGF6 are highly conserved between chick, human, mouse and zebrafish. FGF7 is similarly conserved except for the zebrafish, which has considerably diverged.

A TGFß-Smad4-Fgf6 signaling cascade controls myogenic differentiation and myoblast fusion during tongue development.

The tongue is a muscular organ and plays a crucial role in speech, deglutition and taste. Despite the important physiological functions of the tongue, little is known about the regulatory mechanisms of tongue muscle development. TGFß family members play important roles in regulating myogenesis, but the functional significance of Smad-dependent TGFß signaling in regulating tongue skeletal muscle development remains unclear. In this study, we have investigated Smad4-mediated TGFß signaling in the development of occipital somite-derived myogenic progenitors during tongue morphogenesis through tissue-specific inactivation of Smad4 (using Myf5-Cre;Smad4(flox/flox) mice). During the initiation of tongue development, cranial neural crest (CNC) cells occupy the tongue buds before myogenic progenitors migrate into the tongue primordium, suggesting that CNC cells play an instructive role in guiding tongue muscle development. Moreover, ablation of Smad4 results in defects in myogenic terminal differentiation and myoblast fusion. Despite compromised muscle differentiation, tendon formation appears unaffected in the tongue of Myf5-Cre;Smad4(flox/flox) mice, suggesting that the differentiation and maintenance of CNC-derived tendon cells are independent of Smad4-mediated signaling in myogenic cells in the tongue. Furthermore, loss of Smad4 results in a significant reduction in expression of several members of the FGF family, including Fgf6 and Fgfr4. Exogenous Fgf6 partially rescues the tongue myoblast fusion defect of Myf5-Cre;Smad4(flox/flox) mice. Taken together, our study demonstrates that a TGFß-Smad4-Fgf6 signaling cascade plays a crucial role in myogenic cell fate determination and lineage progression during tongue myogenesis.

Pipeline for large-scale microdroplet bisulfite PCR-based sequencing allows the tracking of hepitype evolution in tumors.

Cytosine methylation provides an epigenetic level of cellular plasticity that is important for development, differentiation and cancerogenesis. We adopted microdroplet PCR to bisulfite treated target DNA in combination with second generation sequencing to simultaneously assess DNA sequence and methylation. We show measurement of methylation status in a wide range of target sequences (total 34 kb) with an average coverage of 95% (median 100%) and good correlation to the opposite strand (rho = 0.96) and to pyrosequencing (rho = 0.87). Data from lymphoma and colorectal cancer samples for SNRPN (imprinted gene), FGF6 (demethylated in the cancer samples) and HS3ST2 (methylated in the cancer samples) serve as a proof of principle showing the integration of SNP data and phased DNA-methylation information into "hepitypes" and thus the analysis of DNA methylation phylogeny in the somatic evolution of cancer.

Eccentric stimulation reveals an involvement of FGF6 in muscle resistance to mechanical stress.

The objective of this report was to analyse a potential role for FGF6 in muscle resistance to mechanical stress. Normal or regenerating muscles of FGF6 (-/-) mice versus wild-type mice were submitted to different protocols of damaging eccentric contractions (eccentric electrostimulation and intermittent downhill exercise). Then muscular structural properties were analysed by histological and immunochemistry techniques to evaluate the post-injury muscle recovery; their muscle contractile parameters (maximal tetanic force, kinetics properties and fatigue resistance) were assessed. The absence of FGF6 causes (1) a fast-to-slow myofibre type switch in adult control and regenerating Tibialis anterior (TA) muscle; (2) muscle weakness in regenerating muscles in animals submitted to eccentric exercise protocols due to aberrant extensive necrotic zones. These observations point out a crucial and unexpected role for FGF6 in muscle integrity and muscle protection against mechanical stress.