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Yasuhiko Kawakami - One of the best experts on this subject based on the ideXlab platform.
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development of the proximal anterior skeletal elements in the mouse Hindlimb is regulated by a transcriptional and signaling network controlled by sall4
Genetics, 2020Co-Authors: Katherine Q Chen, Hiroko Kawakami, Naoyuki Tahara, Ryuichi Nishinakamura, Aaron Anderson, Sho Kawakami, Pier Paolo Pandolfi, Yasuhiko KawakamiAbstract:The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in Hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf We found that Sall4 regulates Plzf expression prior to Hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout Hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in Hindlimbs.
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Gata6 restricts Isl1 to the posterior of nascent Hindlimb buds through Isl1 cis-regulatory modules.
Developmental Biology, 2018Co-Authors: Naoyuki Tahara, Yasuhiko Kawakami, Ryutaro Akiyama, Hiroko Kawakami, Joshua Theisen, Julia Wong, Daniel J. GarryAbstract:Abstract Isl1 is required for two processes during Hindlimb development: initiation of the processes directing Hindlimb development in the lateral plate mesoderm and configuring posterior Hindlimb field in the nascent Hindlimb buds. During these processes, Isl1 expression is restricted to the posterior mesenchyme of Hindlimb buds. How this dynamic change in Isl1 expression is regulated remains unknown. We found that two evolutionarily conserved sequences, located 3’ to the Isl1 gene, regulate LacZ transgene expression in the Hindlimb-forming region in mouse embryos. Both sequences contain GATA binding motifs, and expression pattern analysis identified that Gata6 is expressed in the flank and the anterior portion of nascent Hindlimb buds. Recent studies have shown that conditional inactivation of Gata6 in mice causes Hindlimb-specific pre-axial polydactyly, indicating a role of Gata6 in anterior-posterior patterning of Hindlimbs. We studied whether Gata6 restricts Isl1 in the nascent Hindlimb bud through the cis-regulatory modules. In vitro experiments demonstrate that GATA6 binds to the conserved GATA motifs in the cis-regulatory modules. GATA6 repressed expression of a luciferase reporter that contains the cis-regulatory modules by synergizing with Zfpm2. Analyses of Gata6 mutant embryos showed that ISL1 levels are higher in the anterior of nascent Hindlimb buds than in wild type. Moreover, we detected a greater number of Isl1-transcribing cells in the anterior of nascent Hindlimb buds in Gata6 mutants. Our results support a model in which Gata6 contributes to repression of Isl1 expression in the anterior of nascent Hindlimb buds.
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sall4 gli3 system in early limb progenitors is essential for the development of limb skeletal elements
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Ryutaro Akiyama, Hiroko Kawakami, Julia Wong, Isao Oishi, Ryuichi Nishinakamura, Yasuhiko KawakamiAbstract:Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the Hindlimb. We found that Gli3 expression is reduced in Sall4 mutant Hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent Hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent Hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and Hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and Hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.
Hiroko Kawakami - One of the best experts on this subject based on the ideXlab platform.
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development of the proximal anterior skeletal elements in the mouse Hindlimb is regulated by a transcriptional and signaling network controlled by sall4
Genetics, 2020Co-Authors: Katherine Q Chen, Hiroko Kawakami, Naoyuki Tahara, Ryuichi Nishinakamura, Aaron Anderson, Sho Kawakami, Pier Paolo Pandolfi, Yasuhiko KawakamiAbstract:The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in Hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf We found that Sall4 regulates Plzf expression prior to Hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout Hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in Hindlimbs.
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Gata6 restricts Isl1 to the posterior of nascent Hindlimb buds through Isl1 cis-regulatory modules.
Developmental Biology, 2018Co-Authors: Naoyuki Tahara, Yasuhiko Kawakami, Ryutaro Akiyama, Hiroko Kawakami, Joshua Theisen, Julia Wong, Daniel J. GarryAbstract:Abstract Isl1 is required for two processes during Hindlimb development: initiation of the processes directing Hindlimb development in the lateral plate mesoderm and configuring posterior Hindlimb field in the nascent Hindlimb buds. During these processes, Isl1 expression is restricted to the posterior mesenchyme of Hindlimb buds. How this dynamic change in Isl1 expression is regulated remains unknown. We found that two evolutionarily conserved sequences, located 3’ to the Isl1 gene, regulate LacZ transgene expression in the Hindlimb-forming region in mouse embryos. Both sequences contain GATA binding motifs, and expression pattern analysis identified that Gata6 is expressed in the flank and the anterior portion of nascent Hindlimb buds. Recent studies have shown that conditional inactivation of Gata6 in mice causes Hindlimb-specific pre-axial polydactyly, indicating a role of Gata6 in anterior-posterior patterning of Hindlimbs. We studied whether Gata6 restricts Isl1 in the nascent Hindlimb bud through the cis-regulatory modules. In vitro experiments demonstrate that GATA6 binds to the conserved GATA motifs in the cis-regulatory modules. GATA6 repressed expression of a luciferase reporter that contains the cis-regulatory modules by synergizing with Zfpm2. Analyses of Gata6 mutant embryos showed that ISL1 levels are higher in the anterior of nascent Hindlimb buds than in wild type. Moreover, we detected a greater number of Isl1-transcribing cells in the anterior of nascent Hindlimb buds in Gata6 mutants. Our results support a model in which Gata6 contributes to repression of Isl1 expression in the anterior of nascent Hindlimb buds.
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sall4 gli3 system in early limb progenitors is essential for the development of limb skeletal elements
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Ryutaro Akiyama, Hiroko Kawakami, Julia Wong, Isao Oishi, Ryuichi Nishinakamura, Yasuhiko KawakamiAbstract:Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the Hindlimb. We found that Gli3 expression is reduced in Sall4 mutant Hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent Hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent Hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and Hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and Hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.
Ryuichi Nishinakamura - One of the best experts on this subject based on the ideXlab platform.
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development of the proximal anterior skeletal elements in the mouse Hindlimb is regulated by a transcriptional and signaling network controlled by sall4
Genetics, 2020Co-Authors: Katherine Q Chen, Hiroko Kawakami, Naoyuki Tahara, Ryuichi Nishinakamura, Aaron Anderson, Sho Kawakami, Pier Paolo Pandolfi, Yasuhiko KawakamiAbstract:The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in Hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf We found that Sall4 regulates Plzf expression prior to Hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout Hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in Hindlimbs.
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sall4 gli3 system in early limb progenitors is essential for the development of limb skeletal elements
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Ryutaro Akiyama, Hiroko Kawakami, Julia Wong, Isao Oishi, Ryuichi Nishinakamura, Yasuhiko KawakamiAbstract:Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the Hindlimb. We found that Gli3 expression is reduced in Sall4 mutant Hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent Hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent Hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and Hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and Hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.
Ryutaro Akiyama - One of the best experts on this subject based on the ideXlab platform.
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Gata6 restricts Isl1 to the posterior of nascent Hindlimb buds through Isl1 cis-regulatory modules.
Developmental Biology, 2018Co-Authors: Naoyuki Tahara, Yasuhiko Kawakami, Ryutaro Akiyama, Hiroko Kawakami, Joshua Theisen, Julia Wong, Daniel J. GarryAbstract:Abstract Isl1 is required for two processes during Hindlimb development: initiation of the processes directing Hindlimb development in the lateral plate mesoderm and configuring posterior Hindlimb field in the nascent Hindlimb buds. During these processes, Isl1 expression is restricted to the posterior mesenchyme of Hindlimb buds. How this dynamic change in Isl1 expression is regulated remains unknown. We found that two evolutionarily conserved sequences, located 3’ to the Isl1 gene, regulate LacZ transgene expression in the Hindlimb-forming region in mouse embryos. Both sequences contain GATA binding motifs, and expression pattern analysis identified that Gata6 is expressed in the flank and the anterior portion of nascent Hindlimb buds. Recent studies have shown that conditional inactivation of Gata6 in mice causes Hindlimb-specific pre-axial polydactyly, indicating a role of Gata6 in anterior-posterior patterning of Hindlimbs. We studied whether Gata6 restricts Isl1 in the nascent Hindlimb bud through the cis-regulatory modules. In vitro experiments demonstrate that GATA6 binds to the conserved GATA motifs in the cis-regulatory modules. GATA6 repressed expression of a luciferase reporter that contains the cis-regulatory modules by synergizing with Zfpm2. Analyses of Gata6 mutant embryos showed that ISL1 levels are higher in the anterior of nascent Hindlimb buds than in wild type. Moreover, we detected a greater number of Isl1-transcribing cells in the anterior of nascent Hindlimb buds in Gata6 mutants. Our results support a model in which Gata6 contributes to repression of Isl1 expression in the anterior of nascent Hindlimb buds.
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sall4 gli3 system in early limb progenitors is essential for the development of limb skeletal elements
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Ryutaro Akiyama, Hiroko Kawakami, Julia Wong, Isao Oishi, Ryuichi Nishinakamura, Yasuhiko KawakamiAbstract:Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the Hindlimb. We found that Gli3 expression is reduced in Sall4 mutant Hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent Hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent Hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and Hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and Hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.
Atsushi Kuroiwa - One of the best experts on this subject based on the ideXlab platform.
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Anatomical integration of the sacral–Hindlimb unit coordinated by GDF11 underlies variation in Hindlimb positioning in tetrapods
Nature Ecology & Evolution, 2017Co-Authors: Yoshiyuki Matsubara, Tatsuya Hirasawa, Shiro Egawa, Ayumi Hattori, Takaya Suganuma, Yuhei Kohara, Tatsuya Nagai, Koji Tamura, Shigeru Kuratani, Atsushi KuroiwaAbstract:Elucidating how body parts from different primordia are integrated during development is essential for understanding the nature of morphological evolution. In tetrapod evolution, while the position of the Hindlimb has diversified along with the vertebral formula, the mechanism responsible for this coordination has not been well understood. However, this synchronization suggests the presence of an evolutionarily conserved developmental mechanism that coordinates the positioning of the Hindlimb skeleton derived from the lateral plate mesoderm with that of the sacral vertebrae derived from the somites. Here we show that GDF11 secreted from the posterior axial mesoderm is a key factor in the integration of sacral vertebrae and Hindlimb positioning by inducing Hox gene expression in two different primordia. Manipulating the onset of GDF11 activity altered the position of the Hindlimb in chicken embryos, indicating that the onset of Gdf11 expression is responsible for the coordinated positioning of the sacral vertebrae and Hindlimbs. Through comparative analysis with other vertebrate embryos, we also show that each tetrapod species has a unique onset timing of Gdf11 expression, which is tightly correlated with the anteroposterior levels of the Hindlimb bud. We conclude that the evolutionary diversity of Hindlimb positioning resulted from heterochronic shifts in Gdf11 expression, which led to coordinated shifts in the sacral-Hindlimb unit along the anteroposterior axis.
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anatomical integration of the sacral Hindlimb unit coordinated by gdf11 underlies variation in Hindlimb positioning in tetrapods
Nature Ecology and Evolution, 2017Co-Authors: Yoshiyuki Matsubara, Tatsuya Hirasawa, Shiro Egawa, Ayumi Hattori, Takaya Suganuma, Yuhei Kohara, Tatsuya Nagai, Koji Tamura, Shigeru Kuratani, Atsushi KuroiwaAbstract:Elucidating how body parts from different primordia are integrated during development is essential for understanding the nature of morphological evolution. In tetrapod evolution, while the position of the Hindlimb has diversified along with the vertebral formula, the mechanism responsible for this coordination has not been well understood. However, this synchronization suggests the presence of an evolutionarily conserved developmental mechanism that coordinates the positioning of the Hindlimb skeleton derived from the lateral plate mesoderm with that of the sacral vertebrae derived from the somites. Here we show that GDF11 secreted from the posterior axial mesoderm is a key factor in the integration of sacral vertebrae and Hindlimb positioning by inducing Hox gene expression in two different primordia. Manipulating the onset of GDF11 activity altered the position of the Hindlimb in chicken embryos, indicating that the onset of Gdf11 expression is responsible for the coordinated positioning of the sacral vertebrae and Hindlimbs. Through comparative analysis with other vertebrate embryos, we also show that each tetrapod species has a unique onset timing of Gdf11 expression, which is tightly correlated with the anteroposterior levels of the Hindlimb bud. We conclude that the evolutionary diversity of Hindlimb positioning resulted from heterochronic shifts in Gdf11 expression, which led to coordinated shifts in the sacral-Hindlimb unit along the anteroposterior axis.