The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Nobuyuki Itoh - One of the best experts on this subject based on the ideXlab platform.
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Roles of FGF Signals in Heart Development, Health, and Disease.
Frontiers in Cell and Developmental Biology, 2016Co-Authors: Nobuyuki Itoh, Yoshiaki Nakayama, Hiroya Ohta, Morichika KonishiAbstract:The heart provides the body with oxygen and nutrients and assists in the removal of metabolic waste through the blood vessels of the circulatory system. It is the first organ to form during embryonic morphogenesis. FGFs with diverse functions in development, health, and disease are signaling proteins, mostly as paracrine growth factors or endocrine hormones. The human/mouse FGF family comprises 22 members. Findings obtained from mouse models and human diseases with FGF signaling disorders have indicated that several FGFs are involved in heart development, health, and disease. Paracrine FGFs including FGF8, FGF9, FGF10, and FGF16 act as paracrine signals in embryonic heart development. In addition, paracrine FGFs including FGF2, FGF9, FGF10, and FGF16 play roles as paracrine signals in postnatal heart pathophysiology. Although FGF15/19, FGF21, and FGF23 are typical endocrine FGFs, they mainly function as paracrine signals in heart development or pathophysiology. In heart diseases, serum FGF15/19 levels or FGF21 and FGF23 levels decrease or increase, respectively, indicating their possible roles in heart pathophysiology. FGF2 and FGF10 also stimulate the cardiac differentiation of cultured stem cells and cardiac reprogramming of cultured fibroblasts. These findings provide new insights into the roles of FGF signaling in the heart and potential therapeutic strategies for cardiac disorders.
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FGF16 is required for specification of gabaergic neurons and oligodendrocytes in the zebrafish forebrain
PLOS ONE, 2014Co-Authors: Ayumi Miyake, Yoshiaki Nakayama, Morichika Konishi, Tatsuya Chitose, Eriko Kamei, Atsuko Murakami, Nobuyuki ItohAbstract:Fibroblast growth factor (Fgf) signaling plays crucial roles in various developmental processes including those in the brain. We examined the role of FGF16 in the formation of the zebrafish brain. The knockdown of FGF16 decreased cell proliferation in the forebrain and midbrain. FGF16 was also essential for development of the ventral telencephalon and diencephalon, whereas FGF16 was not required for dorsoventral patterning in the midbrain. FGF16 was additionally required for the specification and differentiation of γ–aminobutyric acid (GABA)ergic interneurons and oligodendrocytes, but not for those of glutamatergic neurons in the forebrain. Cross talk between Fgf and Hedgehog (Hh) signaling was critical for the specification of GABAergic interneurons and oligodendrocytes. The expression of FGF16 in the forebrain was down-regulated by the inhibition of Hh and Fgf19 signaling, but not by that of Fgf3/Fgf8 signaling. The FGF16 morphant phenotype was similar to that of the fgf19 morphant and embryos blocked Hh signaling. The results of the present study indicate that FGF16 signaling, which is regulated by the downstream pathways of Hh-Fgf19 in the forebrain, is involved in forebrain development.
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angiotensin ii induced cardiac hypertrophy and fibrosis are promoted in mice lacking FGF16
Genes to Cells, 2013Co-Authors: Emi Matsumoto, Morichika Konishi, Kazuwa Nakao, Hiroya Ohta, Sayaka Sasaki, Hideyuki Kinoshita, Takuya Kito, Koichiro Kuwahara, Nobuyuki ItohAbstract:Fibroblast growth factors (Fgfs) are pleiotropic proteins involved in development, repair and metabolism. FGF16 is predominantly expressed in the heart. However, as the heart function is essentially normal in FGF16 knockout mice, its role has remained unclear. To elucidate the pathophysiological role of FGF16 in the heart, we examined angiotensin II-induced cardiac hypertrophy and fibrosis in FGF16 knockout mice. Angiotensin II-induced cardiac hypertrophy and fibrosis were significantly promoted by enhancing Tgf-β1 expression in FGF16 knockout mice. Unexpectedly, the response to cardiac remodeling was apparently opposite to that in Fgf2 knockout mice. These results indicate that FGF16 probably prevents cardiac remodeling, although Fgf2 promotes it. Cardiac FGF16 expression was induced after the induction of Fgf2 expression by angiotensin II. In cultured cardiomyocytes, FGF16 expression was promoted by Fgf2. In addition, FGF16 antagonized Fgf2-induced Tgf-β1 expression in cultured cardiomyocytes and noncardiomyocytes. These results suggest a possible mechanism whereby FGF16 prevents angiotensin II-induced cardiac hypertrophy and fibrosis by antagonizing Fgf2. The present findings should provide new insights into the roles of Fgf signaling in cardiac remodeling.
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Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease
Cell and Tissue Research, 2010Co-Authors: Nobuyuki ItohAbstract:Fibroblast growth factors (Fgfs) are proteins with diverse functions in development, repair, and metabolism. The human Fgf gene family with 22 members can be classified into three groups, canonical, intracellular, and hormone-like Fgf genes. In contrast to canonical and intracellular Fgf s identified in invertebrates and vertebrates, hormone-like Fgf s , Fgf15/19 , Fgf21 , and Fgf23 , are vertebrate-specific. The ancestral gene of hormone-like Fgf s was generated from the ancestral gene of canonical Fgf s by gene duplication early in vertebrate evolution. Later, Fgf15/19 , Fgf21 , and Fgf23 were generated from the ancestral gene by genome duplication events. Canonical Fgfs act as autocrine/paracrine factors in an Fgf receptor (Fgfr)-dependent manner. In contrast, hormone-like Fgfs act as endocrine factors in an Fgfr-dependent manner. Canonical Fgfs have a heparin-binding site necessary for the stable binding of Fgfrs and local signaling. In contrast, hormone-like Fgf s acquired endocrine functions by reducing their heparin-binding affinity during their evolution. Fgf15/19 and Fgf23 require βKlotho and αKlotho as cofactors, respectively. However, Fgf21 might physiologically require neither. Hormone-like Fgfs play roles in metabolism at postnatal stages, although they also play roles in development at embryonic stages. Fgf15/19 regulates bile acid metabolism in the liver. Fgf21 regulates lipid metabolism in the white adipose tissue. Fgf23 regulates serum phosphate and active vitamin D levels. Fgf23 signaling disorders caused by hereditary diseases or tumors result in metabolic disorders. In addition, serum Fgf19 or Fgf21 levels are significantly increased by metabolic disorders. Hormone-like Fgfs are newly emerging and quite unique in their evolution and function.
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FGF16 is required for cardiomyocyte proliferation in the mouse embryonic heart
Developmental Dynamics, 2008Co-Authors: Yuhei Hotta, Morichika Konishi, Kazuwa Nakao, Sayaka Sasaki, Hideyuki Kinoshita, Koichiro Kuwahara, Nobuyuki ItohAbstract:Fibroblast growth factor (Fgf) signaling plays important roles in development and metabolism. Mouse FGF16 was predominantly expressed in cardiomyocytes. To elucidate the physiological roles of FGF16, we generated FGF16 knockout mice. Although the mice were apparently normal and fertile, heart weight and cardiomyocyte cell numbers were slightly decreased at 6 months of age. However, blood pressure, heart rate, and cardiac performance were essentially unchanged. In addition, the expression of most cardiac marker genes examined was also essentially unchanged. However, the expression of Bnp was significantly decreased, indicating potential roles of FGF16 in the heart under pathological conditions. In contrast, the proliferation of embryonic cardiomyocytes was significantly decreased, indicating that FGF16 is a growth factor for these cells. The embryonic heart phenotype is similar to that of the Fgf9 knockout heart, indicating Fgf9 and FGF16 to synergistically act as growth factors for embryonic cardiomyocytes. Developmental Dynamics 237:2947–2954, 2008. © 2008 Wiley-Liss, Inc.
Jongsook Kim Kemper - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of hepatic farnesoid x receptor by fgf19 signaling activated src maintains cholesterol levels and protects from atherosclerosis
Journal of Biological Chemistry, 2019Co-Authors: Sangwon Byun, Byron Kemper, Hyunkyung Jung, Jinjing Chen, Bo Kong, Jongsook Kim KemperAbstract:: The bile acid (BA) nuclear receptor, farnesoid X receptor (FXR/NR1H4), maintains metabolic homeostasis by transcriptional control of numerous genes, including an intestinal hormone, fibroblast growth factor-19 (FGF19; FGF15 in mice). Besides activation by BAs, the gene-regulatory function of FXR is also modulated by hormone or nutrient signaling-induced post-translational modifications. Recently, phosphorylation at Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src was shown to be important for FXR function in BA homeostasis. Here, we examined the role of this FXR phosphorylation in cholesterol regulation. In both hepatic FXR-knockout and FXR-knockdown mice, reconstitution of FXR expression up-regulated cholesterol transport genes for its biliary excretion, including scavenger receptor class B member 1 (Scarb1) and ABC subfamily G member 8 (Abcg5/8), decreased hepatic and plasma cholesterol levels, and increased biliary and fecal cholesterol levels. Of note, these sterol-lowering effects were blunted by substitution of Phe for Tyr-67 in FXR. Moreover, consistent with Src's role in phosphorylating FXR, Src knockdown impaired cholesterol regulation in mice. In hypercholesterolemic apolipoprotein E-deficient mice, expression of FXR, but not Y67F-FXR, ameliorated atherosclerosis, whereas Src down-regulation exacerbated it. Feeding or treatment with an FXR agonist induced Abcg5/8 and Scarb1 expression in WT, but not FGF15-knockout, mice. Furthermore, FGF19 treatment increased occupancy of FXR at Abcg5/8 and Scarb1, expression of these genes, and cholesterol efflux from hepatocytes. These FGF19-mediated effects were blunted by the Y67F-FXR substitution or Src down-regulation or inhibition. We conclude that phosphorylation of hepatic FXR by FGF15/19-induced Src maintains cholesterol homeostasis and protects against atherosclerosis.
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small heterodimer partner and fibroblast growth factor 19 inhibit expression of npc1l1 in mouse intestine and cholesterol absorption
Gastroenterology, 2019Co-Authors: Sangwon Byun, Sunmi Seok, Byron Kemper, Eric H Xu, Jongsook Kim KemperAbstract:Background & Aims The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in the intestines of mice, including their regulation of expression of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and cholesterol absorption. Methods We performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-sequencing analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 were examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice, and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells. Results We found that the genes that regulate lipid and ion transport in intestine, including NPC1L1, were up-regulated and that cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice after refeeding after fasting but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF19 injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-α- and -β-muricholic acids; these changes were not observed in SHP-knockout mice. SREBF2 (sterol regulatory element binding transcription factor 2), which regulates cholesterol, activated transcription of NPC1L1. FGF19 signaling led to phosphorylation of SHP, which inhibited SREBF2 activity. Conclusions Postprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia.
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a postprandial fgf19 shp lsd1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Bo Kong, Jun Ichi Sadoshima, Yang Zhang, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
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A postprandial FGF19‐SHP‐LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy
The EMBO Journal, 2017Co-Authors: Sangwon Byun, Byron Kemper, Bo Kong, Jun Ichi Sadoshima, Jian Ma, Yang Zhang, Jongsook Kim KemperAbstract:Abstract Lysosome‐mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient‐sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed‐state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP‐null mice or LSD1‐depleted mice. In addition, feeding‐mediated autophagy inhibition is attenuated in FGF15‐null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB‐bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1‐mediated demethylation of gene‐activation histone marks H3K4‐me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19‐SHP‐LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient‐rich postprandial conditions.
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MicroRNA-34a and Impaired FGF19/21 Signaling in Obesity.
Vitamins and Hormones Series, 2016Co-Authors: T Fu, Jongsook Kim KemperAbstract:The obesity epidemic and the urgent need for effective and safe drugs to treat obesity-related diseases have greatly increased research interest in the metabolic hormones, fibroblast growth factor-19 (FGF19, FGF15 in mice), and FGF21. FGF19 and FGF21 function as endocrine hormones that play key roles in energy metabolism and counteract obesity. Importantly, in obese humans and lab animals, circulating FGF19 and FGF21 levels are elevated, and metabolic actions of these hormones are impaired but the underlying mechanisms remained unknown. Recent microRNA (miR) studies have revealed that aberrantly elevated miR-34a in obesity directly targets β-Klotho, the obligate coreceptor for both FGF19 and FGF21, and attenuates metabolic signaling of these hormones. In this review, we will discuss recent findings in the miR and FGF19/21 fields, emphasizing the novel function of obesity-associated miR-34a in attenuation of FGF19/21 metabolic actions, and further discuss miRs, including miR-34a, as potential drug targets for obesity-related diseases.
Tomasz Zemojtel - One of the best experts on this subject based on the ideXlab platform.
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Brief Report Further Evidence for FGF16 Truncating Mutations as the Cause of X-Linked Recessive Fusion of Metacarpals 4 / 5
2020Co-Authors: Aleksander Jamsheer, Aleksandra Jakubiak, Tomasz Zemojtel, Magdalena Socha, Peter N Robinson, Stefan MundlosAbstract:Background: Metacarpal 4–5 fusion (MF4; MIM#309630) is a rare congenital malformation of the hand characterized by the partial or complete fusion of the fourth and fifth metacarpals. The anomaly occurs as an isolated trait or part of a genetic syndrome. Recently, we have identified FGF16 nonsense mutations as the underlying cause of isolated X-linked recessive MF4. Methods: In this report, we provide a detailed clinical description of a sporadic male patient showing MF4 in whom we performed Sanger sequencing of the entire coding sequence of FGF16. Results: In addition to MF4 symptoms, the patient presented with generalized joint laxity and hypermobility. FGF16 sequencing detected a novel truncating mutation (c.474_477del; p.E158DfsX25) in exon 3 of the gene. A heterozygous mutation was found in a clinically and radiologically unaffected mother of the proband. Conclusion: Our finding confirms that truncating mutations of FGF16 are causative for X-linked recessive metacarpal 4–5 fusion. Importantly, the mutation detected in this study was located in last exon of the gene (exon 3), like the only two FGF16 disease-causing variants identified to date. Thus, all FGF16 mutations known to give rise to this rare skeletal hand malformation are C-terminal and most probably do not result in a nonsense mediated decay. Additionally, our proband showed mild symptoms of a connective tissue disorder, as some other patients previously reported to have X-linked MF4. Therefore, we suggest that impaired FGF16 function may also be responsible for connective tissue symptoms in MF4 patients.
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Further evidence for FGF16 truncating mutations as the cause of X-linked recessive fusion of metacarpals 4 / 5
Birth Defects Research Part A-clinical and Molecular Teratology, 2014Co-Authors: Aleksander Jamsheer, Aleksandra Jakubiak, Tomasz Zemojtel, Magdalena Socha, Peter N Robinson, Robert Smigiel, Stefan MundlosAbstract:Background Metacarpal 4–5 fusion (MF4; MIM#309630) is a rare congenital malformation of the hand characterized by the partial or complete fusion of the fourth and fifth metacarpals. The anomaly occurs as an isolated trait or part of a genetic syndrome. Recently, we have identified FGF16 nonsense mutations as the underlying cause of isolated X-linked recessive MF4. Methods In this report, we provide a detailed clinical description of a sporadic male patient showing MF4 in whom we performed Sanger sequencing of the entire coding sequence of FGF16. Results In addition to MF4 symptoms, the patient presented with generalized joint laxity and hypermobility. FGF16 sequencing detected a novel truncating mutation (c.474_477del; p.E158DfsX25) in exon 3 of the gene. A heterozygous mutation was found in a clinically and radiologically unaffected mother of the proband. Conclusion Our finding confirms that truncating mutations of FGF16 are causative for X-linked recessive metacarpal 4–5 fusion. Importantly, the mutation detected in this study was located in last exon of the gene (exon 3), like the only two FGF16 disease-causing variants identified to date. Thus, all FGF16 mutations known to give rise to this rare skeletal hand malformation are C-terminal and most probably do not result in a nonsense mediated decay. Additionally, our proband showed mild symptoms of a connective tissue disorder, as some other patients previously reported to have X-linked MF4. Therefore, we suggest that impaired FGF16 function may also be responsible for connective tissue symptoms in MF4 patients. Birth Defects Research (Part A) 100:314–318, 2014. © 2014 Wiley Periodicals, Inc.
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further evidence for FGF16 truncating mutations as the cause of x linked recessive fusion of metacarpals 4 5
Birth Defects Research Part A-clinical and Molecular Teratology, 2014Co-Authors: Aleksander Jamsheer, Aleksandra Jakubiak, Tomasz Zemojtel, Magdalena Socha, Peter N Robinson, Robert Smigiel, Stefan MundlosAbstract:Background Metacarpal 4–5 fusion (MF4; MIM#309630) is a rare congenital malformation of the hand characterized by the partial or complete fusion of the fourth and fifth metacarpals. The anomaly occurs as an isolated trait or part of a genetic syndrome. Recently, we have identified FGF16 nonsense mutations as the underlying cause of isolated X-linked recessive MF4. Methods In this report, we provide a detailed clinical description of a sporadic male patient showing MF4 in whom we performed Sanger sequencing of the entire coding sequence of FGF16. Results In addition to MF4 symptoms, the patient presented with generalized joint laxity and hypermobility. FGF16 sequencing detected a novel truncating mutation (c.474_477del; p.E158DfsX25) in exon 3 of the gene. A heterozygous mutation was found in a clinically and radiologically unaffected mother of the proband. Conclusion Our finding confirms that truncating mutations of FGF16 are causative for X-linked recessive metacarpal 4–5 fusion. Importantly, the mutation detected in this study was located in last exon of the gene (exon 3), like the only two FGF16 disease-causing variants identified to date. Thus, all FGF16 mutations known to give rise to this rare skeletal hand malformation are C-terminal and most probably do not result in a nonsense mediated decay. Additionally, our proband showed mild symptoms of a connective tissue disorder, as some other patients previously reported to have X-linked MF4. Therefore, we suggest that impaired FGF16 function may also be responsible for connective tissue symptoms in MF4 patients. Birth Defects Research (Part A) 100:314–318, 2014. © 2014 Wiley Periodicals, Inc.
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brief report further evidence for FGF16 truncating mutations as the cause of x linked recessive fusion of metacarpals 4 5
2014Co-Authors: Aleksander Jamsheer, Aleksandra Jakubiak, Tomasz Zemojtel, Magdalena Socha, Peter N Robinson, Stefan MundlosAbstract:Background: Metacarpal 4–5 fusion (MF4; MIM#309630) is a rare congenital malformation of the hand characterized by the partial or complete fusion of the fourth and fifth metacarpals. The anomaly occurs as an isolated trait or part of a genetic syndrome. Recently, we have identified FGF16 nonsense mutations as the underlying cause of isolated X-linked recessive MF4. Methods: In this report, we provide a detailed clinical description of a sporadic male patient showing MF4 in whom we performed Sanger sequencing of the entire coding sequence of FGF16. Results: In addition to MF4 symptoms, the patient presented with generalized joint laxity and hypermobility. FGF16 sequencing detected a novel truncating mutation (c.474_477del; p.E158DfsX25) in exon 3 of the gene. A heterozygous mutation was found in a clinically and radiologically unaffected mother of the proband. Conclusion: Our finding confirms that truncating mutations of FGF16 are causative for X-linked recessive metacarpal 4–5 fusion. Importantly, the mutation detected in this study was located in last exon of the gene (exon 3), like the only two FGF16 disease-causing variants identified to date. Thus, all FGF16 mutations known to give rise to this rare skeletal hand malformation are C-terminal and most probably do not result in a nonsense mediated decay. Additionally, our proband showed mild symptoms of a connective tissue disorder, as some other patients previously reported to have X-linked MF4. Therefore, we suggest that impaired FGF16 function may also be responsible for connective tissue symptoms in MF4 patients.
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whole exome sequencing identifies FGF16 nonsense mutations as the cause of x linked recessive metacarpal 4 5 fusion
Journal of Medical Genetics, 2013Co-Authors: Aleksander Jamsheer, Tomasz Zemojtel, Mateusz Kolanczyk, Sigmar Stricker, Jochen Hecht, Peter Krawitz, Sandra C DoelkenAbstract:Background Metacarpal 4–5 fusion (MF4; MIM %309630) is a rare congenital malformation of the hand characterised by the partial or complete fusion of the fourth and fifth metacarpals. The anomaly occurs as an isolated trait or part of a genetic syndrome. Methods To search for disease-causing mutation, whole exome sequencing (WES) was performed on samples from a single trio. Before WES, molecular screening including gene sequencing and array comparative genomic hybridisation was applied. Validation of WES and segregation studies were done using routine Sanger sequencing. Results Exome sequencing detected a nonsense mutation (c.C535T; p.R179X) in exon 3 of the FGF16 gene, which maps to chromosome Xq21.1. Mutational screening of the FGF16 gene performed in an unrelated proband of different ethnicity showed another nonsense mutation in exon 3 (c.C470A; p.S157X). Conclusions This study shows that truncating mutations of FGF16 are associated with X-linked recessive metacarpal 4–5 fusion. The study provides evidence for the involvement of FGF16 in the fine tuning of the human skeleton of the hand.
Masaru Katoh - One of the best experts on this subject based on the ideXlab platform.
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Cancer genomics and genetics of FGFR2 (Review)
International Journal of Oncology, 2020Co-Authors: Masaru KatohAbstract:FGFR2 gene encodes FGFR2b in epithelial cells, and FGFR2c in mesenchymal cells. FGFR2b is a high affinity receptor for FGF1, FGF3, FGF7, FGF10 and FGF22, while FGFR2c for FGF1, FGF2, FGF4, FGF6, FGF9, FGF16 and FGF20. Here genomics and genetics of FGFR2, and therapeutics targeted to FGFR2 will be reviewed. Single nucleotide polymorphisms (SNPs) of FGFR2 are associated with increased risk of breast cancer. Gene amplification or missense mutation of FGFR2 occurs in gastric cancer, lung cancer, breast cancer, ovarian cancer, and endometrial cancer. Genetic alterations of FGFR2 induce aberrant FGFR2 signaling activation due to release of FGFR2 from autoinhibition, or creation of FGF signaling autocrine loop. Class switch of FGFR2b to FGFR2c is associated with more malignant phenotype. FGF and canonical WNT signals synergize during mammary carcinogenesis, but counteract during osteogenesis and adipogenesis. Among PD173074, SU5402, and AZD2171 functioning as FGFR inhibitors, AZD2171 is the most promising anti-cancer drug. Cancer genomics and genetics are utilized to predict cancer-driving pathway for therapeutic optimization. FGFR2ome is defined as a complete data set of SNP, copy number variation (CNV), missense mutation, gene amplification, and predominant isoform of FGFR2. FGFR2ome analyses in patients with several tumor types among various populations should be carried out to establish integrative database of FGFR2 for the rational clinical application of FGFR2-targeted cancer therapy.
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FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells.
International Journal of Molecular Medicine, 2006Co-Authors: Yuriko Katoh, Masaru KatohAbstract:: WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-beta-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/beta-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEF-binding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine.
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comparative genomics on FGF16 orthologs
International Journal of Molecular Medicine, 2005Co-Authors: Yuriko Katoh, Masaru KatohAbstract:Abstract We have previously reported comparative genomics analyses on FGF3, FGF4, FGF6, FGF7, FGF8, FGF10, FGF11, FGF17, FGF18, FGF19, FGF20, FGF22 and FGF23 genes. Here, we performed comparative genomics analyses on FGF1, FGF2, FGF5, FGF9, FGF12, FGF13, FGF14, FGF16 and FGF21 genes, and further characterized the FGF16 gene. Chimpanzee FGF16, chicken FGF16, and zebrafish FGF16 genes were identified within NW_121938.1, NW_060344.1, and CR855117.3 genome sequences, respectively. Chimpanzee FGF16 (207 aa), chicken FGF16 (207 aa), and zebrafish FGF16 (203 aa) showed 100%, 89.9%, and 79.2% total amino-acid identity with human FGF16. Because FGF16, FGF9, and FGF20 constitute FGF subfamily without N-terminal signal peptide, we next searched for uncharacterized FGF9 or FGF20 orthologs. Zebrafish fgf9 gene was identified within BX927112.11 genome sequence, and chicken fgf20 gene within NW_060349.1 genome sequence. Although N-terminal part was divergent, middle and C-terminal parts were well conserved among vertebrate FGF16, FGF9 and FGF20 orthologs. Phylogenetic analyses revealed that zebrafish fgf9 and fgf20 were more related to each other than to their chicken or mammalian orthologs. TCF/LEF binding site and TATA box were well conserved among the human FGF16, rat FGF16, and mouse FGF16 promoters. Because nuclear complex consisting of TCF/LEF (TCF1, TCF3, TCF4 or LEF1), beta-catenin, PYGO (PYGO1 or PYGO2) and Legless (BCL9 or BCL9L) binds to the TCF/LEF-binding site to up-regulate WNT/beta-catenin target genes, FGF16 gene was characterized as the evolutionarily conserved target of the WNT/beta-catenin signaling pathway, just like FGF18 and FGF20 genes. These facts indicate that FGF16, FGF18 and FGF20 are pharmacogenomics targets in the field of oncology and regenerative medicine.
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evolutionary conservation of ccnd1 oraov1 fgf19 fgf4 locus from zebrafish to human
International Journal of Molecular Medicine, 2003Co-Authors: Masuko Katoh, Masaru KatohAbstract:Abstract The CCND1-ORAOV1-FGF19-FGF4-FGF3-FLJ10261-FADD-PPFIA1-EMS1 locus on human chromosome 11q13 is frequently amplified in esophageal cancer, breast cancer, and bladder tumors. FGF19, FGF4 and FGF3 genes are implicated in embryogenesis and carcinogenesis. We proposed in 2002 the hypothesis that mouse Fgf15 might be the ortholog of human FGF19 based on comparative genomics. Here, we identified zebrafish fgf19 and oraov1 genes by using bioinformatics to demonstrate the hypothesis. Zebrafish fgf19 gene, consisting of three exons, was located around nucleotide position 121802-124963 of zebrafish genome draft sequence AL929586.12 in the reverse orientation. Zebrafish fgf19 (209 aa) was more homologous to chicken fgf19 and human FGF19 than to rodent Fgf15. Zebrafish oraov1 gene, consisting of five exons, was located around nucleotide position 112172-115838 of AL929586.12 in the reverse orientation. Zebrafish oraov1 protein (141 aa) was more homologous to human ORAOV1 than to rodent Oraov1. The CCND1-ORAOV1-FGF19-FGF4 locus was well conserved between human and zebrafish genomes in the order of genes, in the direction of genes, and in the exon-intron structure. Rat Ccnd1-Oraov1-Fgf15-Fgf4 locus was synthenic to mouse Ccnd1-Oraov1 (also known as 2210010N10Rik)-Fgf15-Fgf4 locus. Fgf15, homologous to human FGF19 and zebrafish fgf19, was located on the synthenic locus of human FGF19 and zebrafish fgf19 within rodent genomes. Based on the evolutionary conservation of the CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human, it was concluded that Fgf15 gene is the rodent ortholog of human FGF19 gene.
Morichika Konishi - One of the best experts on this subject based on the ideXlab platform.
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Roles of FGF Signals in Heart Development, Health, and Disease.
Frontiers in Cell and Developmental Biology, 2016Co-Authors: Nobuyuki Itoh, Yoshiaki Nakayama, Hiroya Ohta, Morichika KonishiAbstract:The heart provides the body with oxygen and nutrients and assists in the removal of metabolic waste through the blood vessels of the circulatory system. It is the first organ to form during embryonic morphogenesis. FGFs with diverse functions in development, health, and disease are signaling proteins, mostly as paracrine growth factors or endocrine hormones. The human/mouse FGF family comprises 22 members. Findings obtained from mouse models and human diseases with FGF signaling disorders have indicated that several FGFs are involved in heart development, health, and disease. Paracrine FGFs including FGF8, FGF9, FGF10, and FGF16 act as paracrine signals in embryonic heart development. In addition, paracrine FGFs including FGF2, FGF9, FGF10, and FGF16 play roles as paracrine signals in postnatal heart pathophysiology. Although FGF15/19, FGF21, and FGF23 are typical endocrine FGFs, they mainly function as paracrine signals in heart development or pathophysiology. In heart diseases, serum FGF15/19 levels or FGF21 and FGF23 levels decrease or increase, respectively, indicating their possible roles in heart pathophysiology. FGF2 and FGF10 also stimulate the cardiac differentiation of cultured stem cells and cardiac reprogramming of cultured fibroblasts. These findings provide new insights into the roles of FGF signaling in the heart and potential therapeutic strategies for cardiac disorders.
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FGF16 is required for specification of gabaergic neurons and oligodendrocytes in the zebrafish forebrain
PLOS ONE, 2014Co-Authors: Ayumi Miyake, Yoshiaki Nakayama, Morichika Konishi, Tatsuya Chitose, Eriko Kamei, Atsuko Murakami, Nobuyuki ItohAbstract:Fibroblast growth factor (Fgf) signaling plays crucial roles in various developmental processes including those in the brain. We examined the role of FGF16 in the formation of the zebrafish brain. The knockdown of FGF16 decreased cell proliferation in the forebrain and midbrain. FGF16 was also essential for development of the ventral telencephalon and diencephalon, whereas FGF16 was not required for dorsoventral patterning in the midbrain. FGF16 was additionally required for the specification and differentiation of γ–aminobutyric acid (GABA)ergic interneurons and oligodendrocytes, but not for those of glutamatergic neurons in the forebrain. Cross talk between Fgf and Hedgehog (Hh) signaling was critical for the specification of GABAergic interneurons and oligodendrocytes. The expression of FGF16 in the forebrain was down-regulated by the inhibition of Hh and Fgf19 signaling, but not by that of Fgf3/Fgf8 signaling. The FGF16 morphant phenotype was similar to that of the fgf19 morphant and embryos blocked Hh signaling. The results of the present study indicate that FGF16 signaling, which is regulated by the downstream pathways of Hh-Fgf19 in the forebrain, is involved in forebrain development.
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angiotensin ii induced cardiac hypertrophy and fibrosis are promoted in mice lacking FGF16
Genes to Cells, 2013Co-Authors: Emi Matsumoto, Morichika Konishi, Kazuwa Nakao, Hiroya Ohta, Sayaka Sasaki, Hideyuki Kinoshita, Takuya Kito, Koichiro Kuwahara, Nobuyuki ItohAbstract:Fibroblast growth factors (Fgfs) are pleiotropic proteins involved in development, repair and metabolism. FGF16 is predominantly expressed in the heart. However, as the heart function is essentially normal in FGF16 knockout mice, its role has remained unclear. To elucidate the pathophysiological role of FGF16 in the heart, we examined angiotensin II-induced cardiac hypertrophy and fibrosis in FGF16 knockout mice. Angiotensin II-induced cardiac hypertrophy and fibrosis were significantly promoted by enhancing Tgf-β1 expression in FGF16 knockout mice. Unexpectedly, the response to cardiac remodeling was apparently opposite to that in Fgf2 knockout mice. These results indicate that FGF16 probably prevents cardiac remodeling, although Fgf2 promotes it. Cardiac FGF16 expression was induced after the induction of Fgf2 expression by angiotensin II. In cultured cardiomyocytes, FGF16 expression was promoted by Fgf2. In addition, FGF16 antagonized Fgf2-induced Tgf-β1 expression in cultured cardiomyocytes and noncardiomyocytes. These results suggest a possible mechanism whereby FGF16 prevents angiotensin II-induced cardiac hypertrophy and fibrosis by antagonizing Fgf2. The present findings should provide new insights into the roles of Fgf signaling in cardiac remodeling.
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FGF16 is required for cardiomyocyte proliferation in the mouse embryonic heart
Developmental Dynamics, 2008Co-Authors: Yuhei Hotta, Morichika Konishi, Kazuwa Nakao, Sayaka Sasaki, Hideyuki Kinoshita, Koichiro Kuwahara, Nobuyuki ItohAbstract:Fibroblast growth factor (Fgf) signaling plays important roles in development and metabolism. Mouse FGF16 was predominantly expressed in cardiomyocytes. To elucidate the physiological roles of FGF16, we generated FGF16 knockout mice. Although the mice were apparently normal and fertile, heart weight and cardiomyocyte cell numbers were slightly decreased at 6 months of age. However, blood pressure, heart rate, and cardiac performance were essentially unchanged. In addition, the expression of most cardiac marker genes examined was also essentially unchanged. However, the expression of Bnp was significantly decreased, indicating potential roles of FGF16 in the heart under pathological conditions. In contrast, the proliferation of embryonic cardiomyocytes was significantly decreased, indicating that FGF16 is a growth factor for these cells. The embryonic heart phenotype is similar to that of the Fgf9 knockout heart, indicating Fgf9 and FGF16 to synergistically act as growth factors for embryonic cardiomyocytes. Developmental Dynamics 237:2947–2954, 2008. © 2008 Wiley-Liss, Inc.
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fgf19 is required for zebrafish lens and retina development
Developmental Biology, 2008Co-Authors: Yoshiaki Nakayama, Ayumi Miyake, Tomotaka Mido, Maya Yoshikawa, Morichika Konishi, Yu Nakagawa, Nobuyuki ItohAbstract:Abstract Fgf signaling plays crucial roles in morphogenesis. Fgf19 is required for zebrafish forebrain development. Here, we examined the roles of Fgf19 in the formation of the lens and retina in zebrafish. Knockdown of Fgf19 caused a size reduction of the lens and the retina, failure of closure of the choroids fissure, and a progressive expansion of the retinal tissue to the midline of the forebrain. Fgf19 expressed in the nasal retina and lens was involved in cell survival but not cell proliferation during embryonic lens and retina development. Fgf19 was essential for the differentiation of lens fiber cells in the lens but not for the neuronal differentiation and lamination in the retina. Loss of nasal fate in the retina caused by the knockdown of Fgf19, expansion of nasal fate in the retina caused by the overexpression of Fgf19 and eye transplantation indicated that Fgf19 in the retina was crucial for the nasal–temporal patterning of the retina that is critical for the guidance of retinal ganglion cell axons. Knockdown of Fgf19 also caused incorrect axon pathfinding. The present findings indicate that Fgf19 positively regulates the patterning and growth of the retina, and the differentiation and growth of the lens in zebrafish.