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Makoto Kuroo - One of the best experts on this subject based on the ideXlab platform.
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klotho and endocrine fibroblast growth factors markers of chronic kidney disease progression and cardiovascular complications
Nephrology Dialysis Transplantation, 2019Co-Authors: Makoto KurooAbstract:Three members of the fibroblast growth factor (FGF) family, FGF19, FGF21 and FGF23, are different from the other members in two major aspects. First, they are actually not growth factors but endocrine factors that regulate various metabolic processes. Second, their physiological receptors are not FGF receptors (FGFRs) but binary complexes of FGFRs and Klotho proteins. FGF23 and FGF21 have emerged as biomarkers that start increasing in early-stage chronic kidney disease (CKD). FGF23 is a bone-derived phosphaturic hormone that binds to the αKlotho-FGFR complex expressed in renal tubules to increase phosphate excretion per nephron. The FGF23 increase is deemed necessary to compensate for the decrease in the nephron number during CKD progression and to maintain the phosphate balance. However, the increase in phosphate excretion per nephron induces renal tubular damage and accelerates nephron loss. CKD progression is also associated with an increase in calciprotein particles (CPPs) in the blood. CPPs are calcium-phosphate nanoparticles with the ability to induce endothelial damage and inflammatory responses. The fact that serum CPP levels are correlated with vascular calcification/stiffness and mortality in CKD patients suggests that CPPs may serve as a 'pathogen' of cardiovascular complications. Like FGF23, FGF21 starts increasing in early-stage CKD. FGF21 is a liver-derived hormone that binds to the βKlotho-FGFR complex expressed in the central nervous system to induce stress responses, including activation of the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis. Thus FGF21 and FGF23 are not merely biomarkers for CKD progression but potential pathogenic agents that accelerate CKD progression and aggravate cardiovascular complications.
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conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor
Journal of Biological Chemistry, 2012Co-Authors: Regina Goetz, Hiroshi Kurosu, Makoto Kuroo, Mutsuko Ohnishi, Serkan Kir, Lei Wang, Johanne Pastor, Weiming Gai, Mohammed S Razzaque, Moosa MohammadiAbstract:FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.
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research resource comprehensive expression atlas of the fibroblast growth factor system in adult mouse
Molecular Endocrinology, 2010Co-Authors: Klementina Fon Tacer, Hiroshi Kurosu, Moosa Mohammadi, Regina Goetz, Makoto Kuroo, Lei Wang, Angie L Bookout, Xunshan Ding, George B John, David J MangelsdorfAbstract:Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.
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the klotho gene family as a regulator of endocrine fibroblast growth factors
Molecular and Cellular Endocrinology, 2009Co-Authors: Hiroshi Kurosu, Makoto KurooAbstract:The Klotho gene encodes a single-pass transmembrane protein and functions as an aging-suppressor gene, which extends lifespan when overexpressed and accelerates the development of aging-like phenotypes when disrupted in mice. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate and vitamin D homeostasis. It has been shown that Klotho-deficient mice and Fgf23 knockout mice exhibit identical phenotypes. This observation led to the identification of Klotho as a cofactor essential for interactions between FGF23 and FGF receptors. In addition to the Klotho-FGF23 axis, recent studies has shown that betaKlotho, a Klotho family protein, also functions as a cofactor required for FGF19 and FGF21 signaling and determines the tissue-specific metabolic activities of FGF19 and FGF21. This review summarizes recent progress in understanding of Klotho and betaKlotho function in the regulation of tissue-specific metabolic activity of the endocrine fibroblast growth factors (FGF19, FGF21, and FGF23).
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tissue specific expression of βklotho and fibroblast growth factor fgf receptor isoforms determines metabolic activity of fgf19 and fgf21
Journal of Biological Chemistry, 2007Co-Authors: Hiroshi Kurosu, Mihwa Choi, Addie S Dickson, Anna V Eliseenkova, Yasushi Ogawa, Moosa Mohammadi, Regina Goetz, Kevin P Rosenblatt, Makoto KurooAbstract:The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1–4). We demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires βKlotho. Both FGF19 and FGF21 can signal through FGFR1–3 bound by βKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the βKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of βKlotho, in combination with particularFGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.
Moosa Mohammadi - One of the best experts on this subject based on the ideXlab platform.
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conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor
Journal of Biological Chemistry, 2012Co-Authors: Regina Goetz, Hiroshi Kurosu, Makoto Kuroo, Mutsuko Ohnishi, Serkan Kir, Lei Wang, Johanne Pastor, Weiming Gai, Mohammed S Razzaque, Moosa MohammadiAbstract:FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.
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plasticity in interactions of fibroblast growth factor 1 fgf1 n terminus with fgf receptors underlies promiscuity of fgf1
Journal of Biological Chemistry, 2012Co-Authors: Andrew Beenken, Anna V Eliseenkova, Omar A Ibrahimi, Shaun K Olsen, Moosa MohammadiAbstract:Abstract Tissue-specific alternative splicing in the second half of Ig-like domain 3 (D3) of fibroblast growth factor receptors 1–3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the “universal FGFR ligand” because it overrides this specificity barrier. To elucidate the molecular basis for FGF1 cross-reactivity with the “b” and “c” splice isoforms of FGFRs, we determined the first crystal structure of FGF1 in complex with an FGFRb isoform, FGFR2b, at 2.1 A resolution. Comparison of the FGF1-FGFR2b structure with the three previously published FGF1-FGFRc structures reveals that plasticity in the interactions of the N-terminal region of FGF1 with FGFR D3 is the main determinant of FGF1 cross-reactivity with both isoforms of FGFRs. In support of our structural data, we demonstrate that substitution of three N-terminal residues (Gly-19, His-25, and Phe-26) of FGF2 (a ligand that does not bind FGFR2b) for the corresponding residues of FGF1 (Phe-16, Asn-22, and Tyr-23) enables the FGF2 triple mutant to bind and activate FGFR2b. These findings taken together with our previous structural data on receptor binding specificity of FGF2, FGF8, and FGF10 conclusively show that sequence divergence at the N termini of FGFs is the primary regulator of the receptor binding specificity and promiscuity of FGFs.
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the structural biology of the fgf19 subfamily
Advances in Experimental Medicine and Biology, 2012Co-Authors: Andrew Beenken, Moosa MohammadiAbstract:The ability of the Fibroblast Growth Factor (FGF) 19 subfamily to signal in an endocrine fashion sets this subfamily apart from the remaining five FGF subfamilies known for their paracrine functions during embryonic development. Compared to the members of paracrine FGF subfamiles, the three members of the FGF19 subfamily, namely FGF19, FGF21 and FGF23, have poor affinity for heparan sulfate (HS) and therefore can diffuse freely in the HS-rich extracellular matrix to enter into the bloodstream. In further contrast to paracrine FGFs, FGF19 subfamily members have unusually poor affinity for their cognate FGF receptors (FGFRs) and therefore cannot bind and activate them in a solely HS-dependent fashion. As a result, the FGF19 subfamily requires α/βklotho coreceptor proteins in order to bind, dimerize and activate their cognate FGFRs. This klotho-dependency also determines the tissue specificity of endocrine FGFs. Recent structural and biochemical studies have begun to shed light onto the molecular basis for the klotho-dependent endocrine mode of action of the FGF19 subfamily. Crystal structures of FGF19 and FGF23 show that the topology of the HS binding site (HBS) of FGF19 subfamily members deviates drastically from the common topology adopted by the paracrine FGFs. The distinct topologies of the HBS of FGF19 and FGF23 prevent HS from direct hydrogen bonding with the backbone atoms of the HBS of these ligands and accordingly decrease the HS binding affinity of this subfamily. Recent biochemical data reveal that the ?klotho ectodomain binds avidly to the ectodomain of FGFR1c, the main cognate FGFR of FGF23, creating a de novo high affinity binding site for the C-terminal tail of FGF23. The isolated FGF23 C-terminus can be used to effectively inhibit the formation of the FGF23-FGFR1c-αklotho complex and alleviate hypophosphatemia in renal phosphate disorders due to elevated levels of FGF23.
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research resource comprehensive expression atlas of the fibroblast growth factor system in adult mouse
Molecular Endocrinology, 2010Co-Authors: Klementina Fon Tacer, Hiroshi Kurosu, Moosa Mohammadi, Regina Goetz, Makoto Kuroo, Lei Wang, Angie L Bookout, Xunshan Ding, George B John, David J MangelsdorfAbstract:Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.
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in vivo genetic evidence for klotho dependent fibroblast growth factor 23 fgf23 mediated regulation of systemic phosphate homeostasis
The FASEB Journal, 2009Co-Authors: Teruyo Nakatani, Moosa Mohammadi, Regina Goetz, Mutsuko Ohnishi, Beate Lanske, Bara Sarraj, Michael Densmore, Takashi Taguchi, Shawkat M RazzaqueAbstract:A major breakthrough in systemic phosphate homeostasis regulation was achieved by the demonstration of strikingly similar physical, morphological, and biochemical phenotypes of fibroblast growth factor 23 (Fgf23) and klotho ablated mice, which led to identification of klotho as an Fgf23 signaling cofactor. Here, we generated Fgf23 and klotho double-knockout (Fgf23−/−/klotho−/−) mice to test the hypothesis whether Fgf23 has a klotho-independent function. Fgf23−/−/klotho−/− mice are viable and have high serum phosphate levels, similar to Fgf23−/− and klotho−/− single-knockout mice. In addition, the Fgf23−/−/klotho−/− mice have increased renal expression of the sodium/phosphate cotransporter NaPi2a and of 1- alpha-hydroxylase concomitant with increased serum levels of 1,25-dihydroxyvitamin-D, as also observed in the Fgf23−/− and klotho−/− mice. Moreover, Fgf23−/−/klotho−/− mice show soft tissue and vascular calcification, severe muscle wasting, hypogonadism, pulmonary emphysema, distention of intestinal wall...
Hiroshi Kurosu - One of the best experts on this subject based on the ideXlab platform.
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conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor
Journal of Biological Chemistry, 2012Co-Authors: Regina Goetz, Hiroshi Kurosu, Makoto Kuroo, Mutsuko Ohnishi, Serkan Kir, Lei Wang, Johanne Pastor, Weiming Gai, Mohammed S Razzaque, Moosa MohammadiAbstract:FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.
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research resource comprehensive expression atlas of the fibroblast growth factor system in adult mouse
Molecular Endocrinology, 2010Co-Authors: Klementina Fon Tacer, Hiroshi Kurosu, Moosa Mohammadi, Regina Goetz, Makoto Kuroo, Lei Wang, Angie L Bookout, Xunshan Ding, George B John, David J MangelsdorfAbstract:Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.
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the klotho gene family as a regulator of endocrine fibroblast growth factors
Molecular and Cellular Endocrinology, 2009Co-Authors: Hiroshi Kurosu, Makoto KurooAbstract:The Klotho gene encodes a single-pass transmembrane protein and functions as an aging-suppressor gene, which extends lifespan when overexpressed and accelerates the development of aging-like phenotypes when disrupted in mice. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate and vitamin D homeostasis. It has been shown that Klotho-deficient mice and Fgf23 knockout mice exhibit identical phenotypes. This observation led to the identification of Klotho as a cofactor essential for interactions between FGF23 and FGF receptors. In addition to the Klotho-FGF23 axis, recent studies has shown that betaKlotho, a Klotho family protein, also functions as a cofactor required for FGF19 and FGF21 signaling and determines the tissue-specific metabolic activities of FGF19 and FGF21. This review summarizes recent progress in understanding of Klotho and betaKlotho function in the regulation of tissue-specific metabolic activity of the endocrine fibroblast growth factors (FGF19, FGF21, and FGF23).
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tissue specific expression of βklotho and fibroblast growth factor fgf receptor isoforms determines metabolic activity of fgf19 and fgf21
Journal of Biological Chemistry, 2007Co-Authors: Hiroshi Kurosu, Mihwa Choi, Addie S Dickson, Anna V Eliseenkova, Yasushi Ogawa, Moosa Mohammadi, Regina Goetz, Kevin P Rosenblatt, Makoto KurooAbstract:The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1–4). We demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires βKlotho. Both FGF19 and FGF21 can signal through FGFR1–3 bound by βKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the βKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of βKlotho, in combination with particularFGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.
David M. Ornitz - One of the best experts on this subject based on the ideXlab platform.
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FGF20 fgfr1 signaling through mapk and pi3k controls sensory progenitor differentiation in the organ of corti
Developmental Dynamics, 2021Co-Authors: Lu M. Yang, David M. OrnitzAbstract:Background Fibroblast Growth Factor 20 (FGF20)-FGF receptor 1 (FGFR1) signaling is essential for cochlear hair cell (HC) and supporting cell (SC) differentiation. In other organ systems, FGFR1 signals through several intracellular pathways including MAPK (ERK), PI3K, phospholipase C ɣ (PLCɣ), and p38. Previous studies implicated MAPK and PI3K pathways in HC and SC development. We hypothesized that one or both would be important downstream mediators of FGF20-FGFR1 signaling for HC differentiation. Results By inhibiting pathways downstream of FGFR1 in cochlea explant cultures, we established that both MAPK and PI3K pathways are required for HC differentiation while PLCɣ and p38 pathways are not. Examining the canonical PI3K pathway, we found that while AKT is necessary for HC differentiation, it is not sufficient to rescue the FGF20-/- phenotype. To determine whether PI3K functions downstream of FGF20, we inhibited Phosphatase and Tensin Homolog (PTEN) in FGF20-/- explants. Overactivation of PI3K resulted in a partial rescue of the FGF20-/- phenotype, demonstrating a requirement for PI3K downstream of FGF20. Consistent with a requirement for the MAPK pathway for FGF20-regulated HC differentiation, we show that treating FGF20-/- explants with FGF9 increased levels of dpERK. Conclusions Together, these data provide evidence that both MAPK and PI3K are important downstream mediators of FGF20-FGFR1 signaling during HC and SC differentiation.
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Analysis of FGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification.
Developmental dynamics : an official publication of the American Association of Anatomists, 2020Co-Authors: Lu M. Yang, Michael Rauchman, Lisa Stout, David M. OrnitzAbstract:BACKGROUND Understanding the mechanisms that regulate hair cell (HC) differentiation in the organ of Corti (OC) is essential to designing genetic therapies for hearing loss due to HC loss or damage. We have previously identified Fibroblast Growth Factor 20 (FGF20) as having a key role in HC and supporting cell differentiation in the mouse OC. To investigate the genetic landscape regulated by FGF20 signaling in OC progenitors, we employ Translating Ribosome Affinity Purification combined with Next Generation RNA Sequencing (TRAPseq) in the FGF20 lineage. RESULTS We show that TRAPseq targeting OC progenitors effectively enriched for RNA from this rare cell population. TRAPseq identified differentially expressed genes (DEGs) downstream of FGF20, including Etv4, Etv5, Etv1, Dusp6, Hey1, Hey2, Heyl, Tectb, Fat3, Cpxm2, Sall1, Sall3, and cell cycle regulators such as Cdc20. Analysis of Cdc20 conditional-null mice identified decreased cochlea length, while analysis of Sall1-null and Sall1-ΔZn2-10 mice, which harbor a mutation that causes Townes-Brocks syndrome, identified a decrease in outer hair cell number. CONCLUSIONS We present two datasets: genes with enriched expression in OC progenitors, and DEGs downstream of FGF20 in the embryonic day 14.5 cochlea. We validate select DEGs via in situ hybridization and in vivo functional studies in mice.
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analysis of FGF20 regulated genes in organ of corti progenitors by translating ribosome affinity purification
bioRxiv, 2020Co-Authors: Lu M. Yang, Michael Rauchman, Lisa Stout, David M. OrnitzAbstract:Background: Understanding the mechanisms that regulate hair cell (HC) differentiation in the organ of Corti (OC) is essential to designing genetic therapies for hearing loss due to HC loss or damage. We have previously identified Fibroblast Growth Factor 20 (FGF20) as having a key role in HC and supporting cell differentiation in the mouse OC. To investigate the genetic landscape regulated by FGF20 signaling in OC progenitors, we employ Translating Ribosome Affinity Purification combined with Next Generation mRNA Sequencing (TRAPseq) in the FGF20 lineage. Results: We show that TRAPseq targeting OC progenitors effectively enriched for mRNA within this rare cell population. TRAPseq identified differentially expressed genes downstream of FGF20, including Etv4, Etv5, Etv1, Dusp6, Hey1, Hey2, Heyl, Tectb, Fat3, Cpxm2, Sall1, Sall3, and cell cycle regulators such as Cdc20. Analysis of Cdc20 conditional-null mice identified decreased cochlea length, while analysis of Sall1-ΔZn2-10 mice, which harbor a mutation that causes Townes-Brocks syndrome, identified a decrease in outer hair cell number. Conclusions: We present two datasets: genes with enriched expression in OC progenitors, and genes regulated by FGF20 in the embryonic day 14.5 cochlea. We validate select differentially expressed genes via in situ hybridization and in vivo functional studies in mice.
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sox2 and FGF20 interact to regulate organ of corti hair cell and supporting cell development in a spatially graded manner
PLOS Genetics, 2019Co-Authors: Lu M. Yang, Sung Ho Huh, Kathryn S E Cheah, David M. OrnitzAbstract:The mouse organ of Corti, housed inside the cochlea, contains hair cells and supporting cells that transduce sound into electrical signals. These cells develop in two main steps: progenitor specification followed by differentiation. Fibroblast Growth Factor (FGF) signaling is important in this developmental pathway, as deletion of FGF receptor 1 (Fgfr1) or its ligand, FGF20, leads to the loss of hair cells and supporting cells from the organ of Corti. However, whether FGF20-FGFR1 signaling is required during specification or differentiation, and how it interacts with the transcription factor Sox2, also important for hair cell and supporting cell development, has been a topic of debate. Here, we show that while FGF20-FGFR1 signaling functions during progenitor differentiation, FGFR1 has an FGF20-independent, Sox2-dependent role in specification. We also show that a combination of reduction in Sox2 expression and FGF20 deletion recapitulates the Fgfr1-deletion phenotype. Furthermore, we uncovered a strong genetic interaction between Sox2 and FGF20, especially in regulating the development of hair cells and supporting cells towards the basal end and the outer compartment of the cochlea. To explain this genetic interaction and its effects on the basal end of the cochlea, we provide evidence that decreased Sox2 expression delays specification, which begins at the apex of the cochlea and progresses towards the base, while FGF20-deletion results in premature onset of differentiation, which begins near the base of the cochlea and progresses towards the apex. Thereby, Sox2 and FGF20 interact to ensure that specification occurs before differentiation towards the cochlear base. These findings reveal an intricate developmental program regulating organ of Corti development along the basal-apical axis of the cochlea.
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sox2 and FGF20 interact to regulate organ of corti hair cell and supporting cell development in a spatially graded manner
bioRxiv, 2019Co-Authors: Lu M. Yang, Sung Ho Huh, Kathryn S E Cheah, David M. OrnitzAbstract:Abstract The mouse organ of Corti develops in two steps: progenitor specification and differentiation. Fibroblast Growth Factor (FGF) signaling is important in this developmental pathway, as deletion of FGF receptor 1 (Fgfr1) or its ligand, FGF20, leads to the loss of hair cells and supporting cells from the organ of Corti. However, whether FGF20-FGFR1 signaling is required during specification or differentiation, and how it interacts with the transcription factor Sox2, also important for hair cell and supporting cell development, has been a topic of debate. Here, we show that while FGF20-FGFR1 signaling functions during progenitor differentiation, FGFR1 has an FGF20-independent, Sox2-dependent role in specification. We also show that a combination of reduction in Sox2 expression and FGF20 deletion recapitulates the Fgfr1-deletion phenotype. Furthermore, we uncovered a strong genetic interaction between Sox2 and FGF20, especially in regulating the development of hair cells and supporting cells towards the basal end and the outer compartment of the organ of Corti. To explain this genetic interaction and its effects on the basal end of the organ of Corti, we provide evidence that decreased Sox2 expression delays specification, which begins at the organ of Corti apex, while FGF20-deletion results in premature onset of differentiation, which begins near the organ of Corti base. Thereby, Sox2 and FGF20 interact to ensure that specification occurs before differentiation towards the cochlear base. These findings reveal an intricate developmental program regulating organ of Corti development along the basal-apical axis of the cochlea. Author summary The mammalian cochlea contains the organ of Corti, a specialized sensory epithelium populated by hair cells and supporting cells that detect sound. Hair cells are susceptible to injury by noise, toxins, and other insults. In mammals, hair cells cannot be regenerated after injury, resulting in permanent hearing loss. Understanding genetic pathways that regulate hair cell development in the mammalian organ of Corti will help in developing methods to regenerate hair cells to treat hearing loss. Many genes are essential for hair cell and supporting cell development in the mouse organ of Corti. Among these are Sox2, Fgfr1, and FGF20. Here, we investigate the relationship between these three genes to further define their roles in development. Interestingly, we found that Sox2 and FGF20 interact to affect hair cell and supporting cell development in a spatially-graded manner. We found that cells toward the outer compartment and the base of the organ of Corti are more strongly affected by the loss of Sox2 and FGF20. We provide evidence that this spatially-graded effect can be partially explained by the roles of the two genes in the precise timing of two sequential stages of organ of Corti development, specification and differentation.
Regina Goetz - One of the best experts on this subject based on the ideXlab platform.
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conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor
Journal of Biological Chemistry, 2012Co-Authors: Regina Goetz, Hiroshi Kurosu, Makoto Kuroo, Mutsuko Ohnishi, Serkan Kir, Lei Wang, Johanne Pastor, Weiming Gai, Mohammed S Razzaque, Moosa MohammadiAbstract:FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.
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research resource comprehensive expression atlas of the fibroblast growth factor system in adult mouse
Molecular Endocrinology, 2010Co-Authors: Klementina Fon Tacer, Hiroshi Kurosu, Moosa Mohammadi, Regina Goetz, Makoto Kuroo, Lei Wang, Angie L Bookout, Xunshan Ding, George B John, David J MangelsdorfAbstract:Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.
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in vivo genetic evidence for klotho dependent fibroblast growth factor 23 fgf23 mediated regulation of systemic phosphate homeostasis
The FASEB Journal, 2009Co-Authors: Teruyo Nakatani, Moosa Mohammadi, Regina Goetz, Mutsuko Ohnishi, Beate Lanske, Bara Sarraj, Michael Densmore, Takashi Taguchi, Shawkat M RazzaqueAbstract:A major breakthrough in systemic phosphate homeostasis regulation was achieved by the demonstration of strikingly similar physical, morphological, and biochemical phenotypes of fibroblast growth factor 23 (Fgf23) and klotho ablated mice, which led to identification of klotho as an Fgf23 signaling cofactor. Here, we generated Fgf23 and klotho double-knockout (Fgf23−/−/klotho−/−) mice to test the hypothesis whether Fgf23 has a klotho-independent function. Fgf23−/−/klotho−/− mice are viable and have high serum phosphate levels, similar to Fgf23−/− and klotho−/− single-knockout mice. In addition, the Fgf23−/−/klotho−/− mice have increased renal expression of the sodium/phosphate cotransporter NaPi2a and of 1- alpha-hydroxylase concomitant with increased serum levels of 1,25-dihydroxyvitamin-D, as also observed in the Fgf23−/− and klotho−/− mice. Moreover, Fgf23−/−/klotho−/− mice show soft tissue and vascular calcification, severe muscle wasting, hypogonadism, pulmonary emphysema, distention of intestinal wall...
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tissue specific expression of βklotho and fibroblast growth factor fgf receptor isoforms determines metabolic activity of fgf19 and fgf21
Journal of Biological Chemistry, 2007Co-Authors: Hiroshi Kurosu, Mihwa Choi, Addie S Dickson, Anna V Eliseenkova, Yasushi Ogawa, Moosa Mohammadi, Regina Goetz, Kevin P Rosenblatt, Makoto KurooAbstract:The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1–4). We demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires βKlotho. Both FGF19 and FGF21 can signal through FGFR1–3 bound by βKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the βKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of βKlotho, in combination with particularFGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.