The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
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.
Nicholas J Cole - One of the best experts on this subject based on the ideXlab platform.
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the evolutionary history of the development of the pelvic fin hindlimb
Journal of Anatomy, 2013Co-Authors: Emily K. Don, Peter D. Currie, Nicholas J ColeAbstract:The arms and legs of man are evolutionarily derived from the paired fins of primitive jawed fish. Few evolutionary changes have attracted as much attention as the origin of tetrapod limbs from the paired fins of ancestral fish. The Hindlimbs of tetrapods are derived from the pelvic fins of ancestral fish. These evolutionary origins can be seen in the examination of shared gene and protein expression patterns during the development of pelvic fins and tetrapod Hindlimbs. The pelvic fins of fish express key limb positioning, limb bud induction and limb outgrowth genes in a similar manner to that seen in hindlimb development of higher vertebrates. We are now at a point where many of the key players in the development of pelvic fins and vertebrate Hindlimbs have been identified and we can now readily examine and compare mechanisms between species. This is yielding fascinating insights into how the developmental programme has altered during evolution and how that relates to anatomical change. The role of pelvic fins has also drastically changed over evolutionary history, from playing a minor role during swimming to developing into robust weight-bearing limbs. In addition, the pelvic fins/Hindlimbs have been lost repeatedly in diverse species over evolutionary time. Here we review the evolution of pelvic fins and Hindlimbs within the context of the changes in anatomical structure and the molecular mechanisms involved.
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The evolutionary history of the development of the pelvic fin/hindlimb
Journal of anatomy, 2012Co-Authors: Emily K. Don, Peter D. Currie, Nicholas J ColeAbstract:The arms and legs of man are evolutionarily derived from the paired fins of primitive jawed fish. Few evolutionary changes have attracted as much attention as the origin of tetrapod limbs from the paired fins of ancestral fish. The Hindlimbs of tetrapods are derived from the pelvic fins of ancestral fish. These evolutionary origins can be seen in the examination of shared gene and protein expression patterns during the development of pelvic fins and tetrapod Hindlimbs. The pelvic fins of fish express key limb positioning, limb bud induction and limb outgrowth genes in a similar manner to that seen in hindlimb development of higher vertebrates. We are now at a point where many of the key players in the development of pelvic fins and vertebrate Hindlimbs have been identified and we can now readily examine and compare mechanisms between species. This is yielding fascinating insights into how the developmental programme has altered during evolution and how that relates to anatomical change. The role of pelvic fins has also drastically changed over evolutionary history, from playing a minor role during swimming to developing into robust weight-bearing limbs. In addition, the pelvic fins/Hindlimbs have been lost repeatedly in diverse species over evolutionary time. Here we review the evolution of pelvic fins and Hindlimbs within the context of the changes in anatomical structure and the molecular mechanisms involved.
Emily K. Don - One of the best experts on this subject based on the ideXlab platform.
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Genetic basis of hindlimb loss in a naturally occurring vertebrate model
Biology open, 2016Co-Authors: Emily K. Don, Thomas E. Hall, Tanya A. De Jong-curtain, Karen Doggett, Benjamin Heng, Andrew P. Badrock, Claire Winnick, Garth A. Nicholson, Gilles J. Guillemin, Peter D. CurrieAbstract:Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod Hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS) of T-box transcription factor 4 (Tbx4) that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A) are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.
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the evolutionary history of the development of the pelvic fin hindlimb
Journal of Anatomy, 2013Co-Authors: Emily K. Don, Peter D. Currie, Nicholas J ColeAbstract:The arms and legs of man are evolutionarily derived from the paired fins of primitive jawed fish. Few evolutionary changes have attracted as much attention as the origin of tetrapod limbs from the paired fins of ancestral fish. The Hindlimbs of tetrapods are derived from the pelvic fins of ancestral fish. These evolutionary origins can be seen in the examination of shared gene and protein expression patterns during the development of pelvic fins and tetrapod Hindlimbs. The pelvic fins of fish express key limb positioning, limb bud induction and limb outgrowth genes in a similar manner to that seen in hindlimb development of higher vertebrates. We are now at a point where many of the key players in the development of pelvic fins and vertebrate Hindlimbs have been identified and we can now readily examine and compare mechanisms between species. This is yielding fascinating insights into how the developmental programme has altered during evolution and how that relates to anatomical change. The role of pelvic fins has also drastically changed over evolutionary history, from playing a minor role during swimming to developing into robust weight-bearing limbs. In addition, the pelvic fins/Hindlimbs have been lost repeatedly in diverse species over evolutionary time. Here we review the evolution of pelvic fins and Hindlimbs within the context of the changes in anatomical structure and the molecular mechanisms involved.
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The evolutionary history of the development of the pelvic fin/hindlimb
Journal of anatomy, 2012Co-Authors: Emily K. Don, Peter D. Currie, Nicholas J ColeAbstract:The arms and legs of man are evolutionarily derived from the paired fins of primitive jawed fish. Few evolutionary changes have attracted as much attention as the origin of tetrapod limbs from the paired fins of ancestral fish. The Hindlimbs of tetrapods are derived from the pelvic fins of ancestral fish. These evolutionary origins can be seen in the examination of shared gene and protein expression patterns during the development of pelvic fins and tetrapod Hindlimbs. The pelvic fins of fish express key limb positioning, limb bud induction and limb outgrowth genes in a similar manner to that seen in hindlimb development of higher vertebrates. We are now at a point where many of the key players in the development of pelvic fins and vertebrate Hindlimbs have been identified and we can now readily examine and compare mechanisms between species. This is yielding fascinating insights into how the developmental programme has altered during evolution and how that relates to anatomical change. The role of pelvic fins has also drastically changed over evolutionary history, from playing a minor role during swimming to developing into robust weight-bearing limbs. In addition, the pelvic fins/Hindlimbs have been lost repeatedly in diverse species over evolutionary time. Here we review the evolution of pelvic fins and Hindlimbs within the context of the changes in anatomical structure and the molecular mechanisms involved.
Reggie V Edgerton - One of the best experts on this subject based on the ideXlab platform.
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use of quadrupedal step training to re engage spinal interneuronal networks and improve locomotor function after spinal cord injury
Brain, 2013Co-Authors: Prithvi K Shah, Guillermo Garciaalias, Jaehoon Choe, Parag Gad, Yury Gerasimenko, Niranjala J K Tillakaratne, Hui Zhong, Roland R Roy, Reggie V EdgertonAbstract:Can lower limb motor function be improved after a spinal cord lesion by re-engaging functional activity of the upper limbs? We addressed this issue by training the forelimbs in conjunction with the Hindlimbs after a thoracic spinal cord hemisection in adult rats. The spinal circuitries were more excitable, and behavioural and electrophysiological analyses showed improved hindlimb function when the forelimbs were engaged simultaneously with the Hindlimbs during treadmill step-training as opposed to training only the Hindlimbs. Neuronal retrograde labelling demonstrated a greater number of propriospinal labelled neurons above and below the thoracic lesion site in quadrupedally versus bipedally trained rats. The results provide strong evidence that actively engaging the forelimbs improves hindlimb function and that one likely mechanism underlying these effects is the reorganization and re-engagement of rostrocaudal spinal interneuronal networks. For the first time, we provide evidence that the spinal interneuronal networks linking the forelimbs and Hindlimbs are amenable to a rehabilitation training paradigm. Identification of this phenomenon provides a strong rationale for proceeding toward preclinical studies for determining whether training paradigms involving upper arm training in concert with lower extremity training can enhance locomotor recovery after neurological damage.
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locomotor ability in spinal rats is dependent on the amount of activity imposed on the Hindlimbs during treadmill training
Journal of Neurotrauma, 2007Co-Authors: John Cha, Roland R Roy, Reggie V Edgerton, Chad Heng, David J Reinkensmeyer, Ray D De LeonAbstract:Studies have shown that treadmill training with body weight support is effective for enhancing locomotor recovery following a complete spinal cord transection (ST) in animals. However, there have been no studies that have investigated the extent that functional recovery in ST animals is dependent on the amount of activity imposed on the Hindlimbs during training. In rats transected as neonates (P5), we used a robotic device to impose either a high or a low amount of hindlimb activity during treadmill training starting 23 days after transection. The rats were trained 5 days per week for 4 weeks. One group (n = 13) received 1000 steps/training session and a second group (n = 13) received 100 steps/training session. During training, the robotic device imposed the maximum amount of weight that each rat could bear on the Hindlimbs, and counted the number of stepping movements during each session. After 4 weeks of training, the number of steps performed during treadmill testing was not significantly different b...
Sarah Mackay - One of the best experts on this subject based on the ideXlab platform.
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postnatal development of the fore and Hindlimbs in the grey short tailed opossum monodelphis domestica
Journal of Anatomy, 2003Co-Authors: Katherine E A Martin, Sarah MackayAbstract:Marsupials are good experimental animals for developmental studies as their offspring are born at a stage comparable to embryonic stages of eutherian species. The South American opossum, Monodelphis domestica, is particularly useful because of its small size and easy maintenance. This study was carried out to compare development of opossum fore- and Hindlimbs during postnatal life, using light microscopy and whole mount alizarin staining. At birth, well-developed mobile forelimbs show cartilage models of bones and myotubular striated muscle fibres. However, Hindlimbs are relatively underdeveloped paddle-like outgrowths. Two days later mesodermal condensations form models of the future hindlimb bones and mononucleate myoblast aggregates are present; by 6 days post partum (dpp) the hindlimb has reached a stage of development similar to that of the forelimb at birth. At this stage, periosteal buds have invaded forelimb long bones and nuclei in forelimb muscle fibres have become displaced to the periphery. The 16 dpp hindlimb shows long bones invaded by periosteal buds and closely packed, striated muscle fibres. Epiphyseal plates are now seen in the forelimb long bones and forelimb muscle fibres show mature characteristics. Musculoskeletal development is well correlated with the functional demands of the limbs during postnatal development in the opossum, which provides an excellent model for investigations into the genes and molecules controlling limb development.