The Experts below are selected from a list of 15873 Experts worldwide ranked by ideXlab platform
Qunlin Gong - One of the best experts on this subject based on the ideXlab platform.
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tert assists GDF11 to rejuvenate senescent vegfr2 cd133 cells in elderly patients with myocardial infarction
Laboratory Investigation, 2019Co-Authors: Lan Zhao, Shaoheng Zhang, Jin Cui, Weiguang Huang, Jiahong Wang, Nannan Chen, Qunlin GongAbstract:Growth differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in rejuvenating old stem cells after acute injury in the elderly population. This study aimed to evaluate the effects of telomerase reverse transcriptase (TERT) on GDF11-mediated rejuvenation of senescent late-outgrowth endothelial progenitor cells (EPCs), defined as VEGFR2+/CD133+ cells, in elderly patients with acute myocardial infarction (AMI). We compared the quantity and capabilities of VEGFR2+/CD133+ cells from old (>60 years), middle-aged (45–60 years), and young (<45 years) AMI patients. The decline in circulating count and survival of VEGFR2+/CD133+ cells with age was accompanied by decrease in their TERT and GDF11 expression levels in patients with AMI. Further, upregulation of TERT could trigger GDF11-mediated rejuvenation of old VEGFR2+/CD133+ cells by renewing their survival and angiogenic abilities through activation of canonical (Smad2/3) and noncanonical (eNOS) signaling pathways. Depletion of GDF11 or TERT caused senescence of young VEGFR2+/CD133+ cells leading to impaired vascular function and angiogenesis in vitro and in vivo, whereas adTERT and rhGDF11 rescued this senescence. TERT cooperates with GDF11 to enhance regenerative capabilities of old VEGFR2+/CD133+ cells. When combined with TERT, GDF11 may represent a potential therapeutic target for the treatment of elderly patients with MI. This study shows how telomerase reverse transcriptase (TERT) assists growth differentiation factor 11 (GDF11) to rejuvenate senescent endothelial progenitor cells via the Smad2/3 and eNOS pathways. Therapeutically, it may be possible to exploit TERT mediated-GDF11 signaling to activate senescent stem cells in the myocardial ischemic microenvironment.
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tert assists GDF11 to rejuvenate senescent vegfr2 cd133 cells in elderly patients with myocardial infarction
Laboratory Investigation, 2019Co-Authors: Lan Zhao, Shaoheng Zhang, Jin Cui, Weiguang Huang, Jiahong Wang, Nannan Chen, Qunlin GongAbstract:Growth differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in rejuvenating old stem cells after acute injury in the elderly population. This study aimed to evaluate the effects of telomerase reverse transcriptase (TERT) on GDF11-mediated rejuvenation of senescent late-outgrowth endothelial progenitor cells (EPCs), defined as VEGFR2+/CD133+ cells, in elderly patients with acute myocardial infarction (AMI). We compared the quantity and capabilities of VEGFR2+/CD133+ cells from old (>60 years), middle-aged (45-60 years), and young (<45 years) AMI patients. The decline in circulating count and survival of VEGFR2+/CD133+ cells with age was accompanied by decrease in their TERT and GDF11 expression levels in patients with AMI. Further, upregulation of TERT could trigger GDF11-mediated rejuvenation of old VEGFR2+/CD133+ cells by renewing their survival and angiogenic abilities through activation of canonical (Smad2/3) and noncanonical (eNOS) signaling pathways. Depletion of GDF11 or TERT caused senescence of young VEGFR2+/CD133+ cells leading to impaired vascular function and angiogenesis in vitro and in vivo, whereas adTERT and rhGDF11 rescued this senescence. TERT cooperates with GDF11 to enhance regenerative capabilities of old VEGFR2+/CD133+ cells. When combined with TERT, GDF11 may represent a potential therapeutic target for the treatment of elderly patients with MI.
Jeh-ping Liu - One of the best experts on this subject based on the ideXlab platform.
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GDF11 facilitates temporal progression of neurogenesis in the developing spinal cord.
Journal of Neuroscience, 2011Co-Authors: Yingtang Shi, Jeh-ping LiuAbstract:Various types of neurons and glia are generated following a precise spatial and temporal order during neurogenesis. The mechanisms that control this sequential generation of neuronal and glial cell types from the same progenitor population are not well understood. Growth differentiation factor 11 (GDF11) belongs to the TGF-β family of proteins and is expressed transiently in newly born neurons adjacent to the progenitor domain in the developing spinal cord. We examined the phenotypes of GDF11 −/− mouse embryos and found that without GDF11, neuronal differentiation in the spinal cord progresses at a slower rate. Higher progenitor proliferation rate, along with a delay in gliogenesis, is also observed in GDF11 −/− spinal cord but only after the peak of GDF11 expression, indicating that GDF11 can cause long-lasting changes in progenitor properties. These changes can be preserved in vitro , as neurospheres derived from GDF11 −/− and wild-type littermates at a stage after, but not before the onset of GDF11 expression, exhibit differences in proliferation and differentiation potential. Moreover, these changes in progenitor properties can be induced in vitro by the addition of GDF11. We also demonstrate that the effects of GDF11 on progenitor cells are associated with its ability to upregulate p57 Kip2 and p27 Kip1 while downregulating Pax6 expression. These results support a model in which GDF11 secreted by newly born neurons in the developing spinal cord facilitates the temporal progression of neurogenesis by acting as a positive feedback signal on the progenitor cells to promote cell cycle exit and decrease proliferation ability, thus changing their differentiation potential.
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The function of growth/differentiation factor 11 (GDF11) in rostrocaudal patterning of the developing spinal cord
Development, 2006Co-Authors: Jeh-ping LiuAbstract:Hoxc family transcription factors are expressed in different domains along the rostrocaudal (RC) axis of the developing spinal cord and they define RC identities of spinal neurons. Our previous study using an in vitro assay system demonstrated that Fgf and GDF11 signals located around Hensen's node of chick embryos have the ability to induce profiled Hoxc protein expression. To investigate the function of GDF11 in RC patterning of the spinal cord in vivo, we expressed GDF11 in chick embryonic spinal cord by in ovo electroporation and found that ectopic expression of GDF11 in the neural tissue causes a rostral displacement of Hoxc protein expression domains, accompanied by rostral shifts in the positions of motoneuron columns and pools. Moreover, ectopic expression of follistatin (Fst), an antagonist of GDF11, has a converse effect and causes caudal displacement of Hox protein expression domains, as well as motoneuron columns and pools. Mouse mutants lacking GDF11 function exhibit a similar caudal displacement of Hox expression domains, but the severity of phenotype increases towards the caudal end of the spinal cord, indicating that the function of GDF11 is more important in the caudal spinal cord. We also provide evidence that GDF11 induces Smad2 phosphorylation and activated Smad2 is able to induce caudal Hox gene expression. These results demonstrate that GDF11 has an important function in determining Hox gene expression domains and RC identity in the caudal spinal cord.
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the function of growth differentiation factor 11 GDF11 in rostrocaudal patterning of the developing spinal cord
Development, 2006Co-Authors: Jeh-ping LiuAbstract:Hoxc family transcription factors are expressed in different domains along the rostrocaudal (RC) axis of the developing spinal cord and they define RC identities of spinal neurons. Our previous study using an in vitro assay system demonstrated that Fgf and GDF11 signals located around Hensen's node of chick embryos have the ability to induce profiled Hoxc protein expression. To investigate the function of GDF11 in RC patterning of the spinal cord in vivo, we expressed GDF11 in chick embryonic spinal cord by in ovo electroporation and found that ectopic expression of GDF11 in the neural tissue causes a rostral displacement of Hoxc protein expression domains, accompanied by rostral shifts in the positions of motoneuron columns and pools. Moreover, ectopic expression of follistatin (Fst), an antagonist of GDF11, has a converse effect and causes caudal displacement of Hox protein expression domains, as well as motoneuron columns and pools. Mouse mutants lacking GDF11 function exhibit a similar caudal displacement of Hox expression domains, but the severity of phenotype increases towards the caudal end of the spinal cord, indicating that the function of GDF11 is more important in the caudal spinal cord. We also provide evidence that GDF11 induces Smad2 phosphorylation and activated Smad2 is able to induce caudal Hox gene expression. These results demonstrate that GDF11 has an important function in determining Hox gene expression domains and RC identity in the caudal spinal cord.
Lan Zhao - One of the best experts on this subject based on the ideXlab platform.
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tert assists GDF11 to rejuvenate senescent vegfr2 cd133 cells in elderly patients with myocardial infarction
Laboratory Investigation, 2019Co-Authors: Lan Zhao, Shaoheng Zhang, Jin Cui, Weiguang Huang, Jiahong Wang, Nannan Chen, Qunlin GongAbstract:Growth differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in rejuvenating old stem cells after acute injury in the elderly population. This study aimed to evaluate the effects of telomerase reverse transcriptase (TERT) on GDF11-mediated rejuvenation of senescent late-outgrowth endothelial progenitor cells (EPCs), defined as VEGFR2+/CD133+ cells, in elderly patients with acute myocardial infarction (AMI). We compared the quantity and capabilities of VEGFR2+/CD133+ cells from old (>60 years), middle-aged (45–60 years), and young (<45 years) AMI patients. The decline in circulating count and survival of VEGFR2+/CD133+ cells with age was accompanied by decrease in their TERT and GDF11 expression levels in patients with AMI. Further, upregulation of TERT could trigger GDF11-mediated rejuvenation of old VEGFR2+/CD133+ cells by renewing their survival and angiogenic abilities through activation of canonical (Smad2/3) and noncanonical (eNOS) signaling pathways. Depletion of GDF11 or TERT caused senescence of young VEGFR2+/CD133+ cells leading to impaired vascular function and angiogenesis in vitro and in vivo, whereas adTERT and rhGDF11 rescued this senescence. TERT cooperates with GDF11 to enhance regenerative capabilities of old VEGFR2+/CD133+ cells. When combined with TERT, GDF11 may represent a potential therapeutic target for the treatment of elderly patients with MI. This study shows how telomerase reverse transcriptase (TERT) assists growth differentiation factor 11 (GDF11) to rejuvenate senescent endothelial progenitor cells via the Smad2/3 and eNOS pathways. Therapeutically, it may be possible to exploit TERT mediated-GDF11 signaling to activate senescent stem cells in the myocardial ischemic microenvironment.
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tert assists GDF11 to rejuvenate senescent vegfr2 cd133 cells in elderly patients with myocardial infarction
Laboratory Investigation, 2019Co-Authors: Lan Zhao, Shaoheng Zhang, Jin Cui, Weiguang Huang, Jiahong Wang, Nannan Chen, Qunlin GongAbstract:Growth differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in rejuvenating old stem cells after acute injury in the elderly population. This study aimed to evaluate the effects of telomerase reverse transcriptase (TERT) on GDF11-mediated rejuvenation of senescent late-outgrowth endothelial progenitor cells (EPCs), defined as VEGFR2+/CD133+ cells, in elderly patients with acute myocardial infarction (AMI). We compared the quantity and capabilities of VEGFR2+/CD133+ cells from old (>60 years), middle-aged (45-60 years), and young (<45 years) AMI patients. The decline in circulating count and survival of VEGFR2+/CD133+ cells with age was accompanied by decrease in their TERT and GDF11 expression levels in patients with AMI. Further, upregulation of TERT could trigger GDF11-mediated rejuvenation of old VEGFR2+/CD133+ cells by renewing their survival and angiogenic abilities through activation of canonical (Smad2/3) and noncanonical (eNOS) signaling pathways. Depletion of GDF11 or TERT caused senescence of young VEGFR2+/CD133+ cells leading to impaired vascular function and angiogenesis in vitro and in vivo, whereas adTERT and rhGDF11 rescued this senescence. TERT cooperates with GDF11 to enhance regenerative capabilities of old VEGFR2+/CD133+ cells. When combined with TERT, GDF11 may represent a potential therapeutic target for the treatment of elderly patients with MI.
Miook Cho - One of the best experts on this subject based on the ideXlab platform.
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variation in zygotic crispr cas9 gene editing outcomes generates novel reporter and deletion alleles at the GDF11 locus
Scientific Reports, 2019Co-Authors: Jill M. Goldstein, Ryan G Walker, Melanie J Mills, Kathleen A. Messemer, Austin Valido, Jordan P. Lewandowski, Paul Besseling, Kyu Ha Lee, Samuel J. Wattrus, Miook ChoAbstract:Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to generate a knock-in GFP reporter mouse at the GDF11 locus. Phenotypic and genomic characterization of founder animals from these injections revealed a subset that contained the correct targeting event and exhibited GFP expression that, within the hematopoietic system, was restricted predominantly to lymphoid cells. Yet, in another subset of founder mice, we detected aberrant integration events at the target site that dramatically and inaccurately shifted hematopoietic GFP expression from the lymphoid to the myeloid lineage. Additionally, we recovered multiple GDF11 deletion alleles that modified the C-terminus of the GDF11 protein. When bred to homozygosity, most of these alleles recapitulated skeletal phenotypes reported previously for GDF11 knockout mice, suggesting that these represent null alleles. However, we also recovered one GDF11 deletion allele that encodes a novel GDF11 variant protein (“GDF11-WE”) predicted to contain two additional amino acids (tryptophan (W) and glutamic acid (E)) at the C-terminus of the mature ligand. Unlike the other GDF11 deletion alleles recovered in this study, homozygosity for the GDF11WE allele did not phenocopy GDF11 knockout skeletal phenotypes. Further investigation using in vivo and in vitro approaches demonstrated that GDF11-WE retains substantial physiological function, indicating that GDF11 can tolerate at least some modifications of its C-terminus and providing unexpected insights into its biochemical activities. Altogether, our study confirms that one-step zygotic injections of CRISPR/Cas gene editing complexes provide a quick and powerful tool to generate gene-modified mouse models. Moreover, our findings underscore the critical importance of thorough characterization and validation of any modified alleles generated by CRISPR, as unintended on-target effects that fail to be detected by simple PCR screening can produce substantially altered phenotypic readouts.
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Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the GDF11 locus.
Scientific Reports, 2019Co-Authors: Jill M. Goldstein, Ryan G Walker, Melanie J Mills, Kathleen A. Messemer, Austin Valido, Jordan P. Lewandowski, Paul Besseling, Kyu Ha Lee, Samuel J. Wattrus, Miook ChoAbstract:Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to generate a knock-in GFP reporter mouse at the GDF11 locus. Phenotypic and genomic characterization of founder animals from these injections revealed a subset that contained the correct targeting event and exhibited GFP expression that, within the hematopoietic system, was restricted predominantly to lymphoid cells. Yet, in another subset of founder mice, we detected aberrant integration events at the target site that dramatically and inaccurately shifted hematopoietic GFP expression from the lymphoid to the myeloid lineage. Additionally, we recovered multiple GDF11 deletion alleles that modified the C-terminus of the GDF11 protein. When bred to homozygosity, most of these alleles recapitulated skeletal phenotypes reported previously for GDF11 knockout mice, suggesting that these represent null alleles. However, we also recovered one GDF11 deletion allele that encodes a novel GDF11 variant protein (“GDF11-WE”) predicted to contain two additional amino acids (tryptophan (W) and glutamic acid (E)) at the C-terminus of the mature ligand. Unlike the other GDF11 deletion alleles recovered in this study, homozygosity for the GDF11WE allele did not phenocopy GDF11 knockout skeletal phenotypes. Further investigation using in vivo and in vitro approaches demonstrated that GDF11-WE retains substantial physiological function, indicating that GDF11 can tolerate at least some modifications of its C-terminus and providing unexpected insights into its biochemical activities. Altogether, our study confirms that one-step zygotic injections of CRISPR/Cas gene editing complexes provide a quick and powerful tool to generate gene-modified mouse models. Moreover, our findings underscore the critical importance of thorough characterization and validation of any modified alleles generated by CRISPR, as unintended on-target effects that fail to be detected by simple PCR screening can produce substantially altered phenotypic readouts.
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Structural basis for potency differences between GDF8 and GDF11.
BMC Biology, 2017Co-Authors: Ryan G Walker, Magdalena Czepnik, Erich J. Goebel, Jason C. Mccoy, Ana Vujic, Miook Cho, Senem Aykul, Kelly L. Walton, Gauthier SchangAbstract:Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.
Ryan G Walker - One of the best experts on this subject based on the ideXlab platform.
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exogenous GDF11 but not gdf8 reduces body weight and improves glucose homeostasis in mice
Scientific Reports, 2020Co-Authors: Ryan G Walker, Ornella Barrandon, Tommaso Poggioli, Sezin Dagdeviren, Shannon H Carroll, Melanie J Mills, Kourtney R Mendello, Yanet Gomez, Francesco S Loffredo, James R PancoastAbstract:Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3-17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis.
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Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the GDF11 locus.
Scientific Reports, 2019Co-Authors: Jill M. Goldstein, Ryan G Walker, Melanie J Mills, Kathleen A. Messemer, Austin Valido, Jordan P. Lewandowski, Paul Besseling, Kyu Ha Lee, Samuel J. Wattrus, Miook ChoAbstract:Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to generate a knock-in GFP reporter mouse at the GDF11 locus. Phenotypic and genomic characterization of founder animals from these injections revealed a subset that contained the correct targeting event and exhibited GFP expression that, within the hematopoietic system, was restricted predominantly to lymphoid cells. Yet, in another subset of founder mice, we detected aberrant integration events at the target site that dramatically and inaccurately shifted hematopoietic GFP expression from the lymphoid to the myeloid lineage. Additionally, we recovered multiple GDF11 deletion alleles that modified the C-terminus of the GDF11 protein. When bred to homozygosity, most of these alleles recapitulated skeletal phenotypes reported previously for GDF11 knockout mice, suggesting that these represent null alleles. However, we also recovered one GDF11 deletion allele that encodes a novel GDF11 variant protein (“GDF11-WE”) predicted to contain two additional amino acids (tryptophan (W) and glutamic acid (E)) at the C-terminus of the mature ligand. Unlike the other GDF11 deletion alleles recovered in this study, homozygosity for the GDF11WE allele did not phenocopy GDF11 knockout skeletal phenotypes. Further investigation using in vivo and in vitro approaches demonstrated that GDF11-WE retains substantial physiological function, indicating that GDF11 can tolerate at least some modifications of its C-terminus and providing unexpected insights into its biochemical activities. Altogether, our study confirms that one-step zygotic injections of CRISPR/Cas gene editing complexes provide a quick and powerful tool to generate gene-modified mouse models. Moreover, our findings underscore the critical importance of thorough characterization and validation of any modified alleles generated by CRISPR, as unintended on-target effects that fail to be detected by simple PCR screening can produce substantially altered phenotypic readouts.
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variation in zygotic crispr cas9 gene editing outcomes generates novel reporter and deletion alleles at the GDF11 locus
Scientific Reports, 2019Co-Authors: Jill M. Goldstein, Ryan G Walker, Melanie J Mills, Kathleen A. Messemer, Austin Valido, Jordan P. Lewandowski, Paul Besseling, Kyu Ha Lee, Samuel J. Wattrus, Miook ChoAbstract:Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to generate a knock-in GFP reporter mouse at the GDF11 locus. Phenotypic and genomic characterization of founder animals from these injections revealed a subset that contained the correct targeting event and exhibited GFP expression that, within the hematopoietic system, was restricted predominantly to lymphoid cells. Yet, in another subset of founder mice, we detected aberrant integration events at the target site that dramatically and inaccurately shifted hematopoietic GFP expression from the lymphoid to the myeloid lineage. Additionally, we recovered multiple GDF11 deletion alleles that modified the C-terminus of the GDF11 protein. When bred to homozygosity, most of these alleles recapitulated skeletal phenotypes reported previously for GDF11 knockout mice, suggesting that these represent null alleles. However, we also recovered one GDF11 deletion allele that encodes a novel GDF11 variant protein (“GDF11-WE”) predicted to contain two additional amino acids (tryptophan (W) and glutamic acid (E)) at the C-terminus of the mature ligand. Unlike the other GDF11 deletion alleles recovered in this study, homozygosity for the GDF11WE allele did not phenocopy GDF11 knockout skeletal phenotypes. Further investigation using in vivo and in vitro approaches demonstrated that GDF11-WE retains substantial physiological function, indicating that GDF11 can tolerate at least some modifications of its C-terminus and providing unexpected insights into its biochemical activities. Altogether, our study confirms that one-step zygotic injections of CRISPR/Cas gene editing complexes provide a quick and powerful tool to generate gene-modified mouse models. Moreover, our findings underscore the critical importance of thorough characterization and validation of any modified alleles generated by CRISPR, as unintended on-target effects that fail to be detected by simple PCR screening can produce substantially altered phenotypic readouts.
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Structural basis for potency differences between GDF8 and GDF11.
BMC Biology, 2017Co-Authors: Ryan G Walker, Magdalena Czepnik, Erich J. Goebel, Jason C. Mccoy, Ana Vujic, Miook Cho, Senem Aykul, Kelly L. Walton, Gauthier SchangAbstract:Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.
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Biochemistry and Biology of GDF11 and Myostatin
Circulation Research, 2016Co-Authors: Ryan G Walker, Tommaso Poggioli, Lida Katsimpardi, Sean M. Buchanan, Lee L. Rubin, Sam Wattrus, Bettina Heidecker, Yick W. Fong, Peter GanzAbstract:Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during developm...
