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Dale R. Sengelaub - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective Effects on the Morphology of Somatic Motoneurons Following the Death of Neighboring Motoneurons: A Role for Microglia?
Developmental neurobiology, 2019Co-Authors: Cory Chew, Brandon J. Kiley, Dale R. SengelaubAbstract:Partial depletion of spinal Motoneuron populations induces dendritic atrophy in neighboring Motoneurons, and treatment with testosterone protects Motoneurons from induced dendritic atrophy. We explored a potential mechanism for this induced atrophy and protection by testosterone, examining the microglial response to partial depletion of Motoneurons. Motoneurons innervating the vastus medialis muscles of adult male rats were killed by intramuscular injection of cholera toxin-conjugated saporin; some saporin-injected rats were treated with testosterone. Microglia were later visualized via immunohistochemical staining, classified as monitoring or activated, and counted stereologically. Partial Motoneuron depletion increased the number of activated microglia in the quadriceps motor pool, and this increase was attenuated with testosterone treatment. The attenuation in microglial response could reflect an effect of testosterone on suppressing microglia activation, potentially sparing Motoneuron dendrites. Alternatively, testosterone could be neuroprotective, sparing Motoneuron dendrites, secondarily resulting in reduced microglial activation. To discriminate between these hypotheses, following partial Motoneuron depletion, rats were treated with minocycline to inhibit microglial activation. Motoneurons innervating the ipsilateral vastus lateralis muscle were later labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed. Reduction of microglial activation by minocycline did not prevent induced dendritic atrophy following partial Motoneuron depletion. Further, reduction of microglial activation by minocycline treatment resulted in dendritic atrophy in intact animals. Together, these findings indicate that the neuroprotective effect of testosterone on dendrites following Motoneuron death is not due to inhibiting microglial activation, and that microglial activity contributes to the normal maintenance of dendritic arbors.
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Neuroprotective actions of androgens on Motoneurons.
Frontiers in neuroendocrinology, 2009Co-Authors: Keith N. Fargo, Eileen M. Foecking, Kathryn J. Jones, Dale R. SengelaubAbstract:Androgens have a variety of protective and therapeutic effects in both the central and peripheral nervous systems. Here we review these effects as they related specifically to spinal and cranial Motoneurons. Early in development, androgens are critical for the formation of important neuromuscular sex differences, decreasing the magnitude of normally occurring cell death in select Motoneuron populations. Throughout the lifespan, androgens also protect against Motoneuron death caused by axonal injury. Surviving Motoneurons also display regressive changes to their neurites as a result of both direct axonal injury and loss of neighboring Motoneurons. Androgen treatment enhances the ability of Motoneurons to recover from these regressive changes and regenerate both axons and dendrites, restoring normal neuromuscular function. Androgens exert these protective effects by acting through a variety of molecular pathways. Recent work has begun to examine how androgen treatment can interact with other treatment strategies in promoting recovery from Motoneuron injury.
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Neuroprotective effects of testosterone on the morphology and function of somatic Motoneurons following the death of neighboring Motoneurons.
The Journal of comparative neurology, 2009Co-Authors: Christine M. Little, Kellie D. Coons, Dale R. SengelaubAbstract:Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have previously shown that partial depletion of Motoneurons from sexually dimorphic, highly androgen-sensitive spinal motor populations induces dendritic atrophy in remaining Motoneurons, and this atrophy is attenuated by treatment with testosterone. To test whether testosterone has similar effects in more typical Motoneurons, we examined potential neuroprotective effects in Motoneurons innervating muscles of the quadriceps. Motoneurons innervating the vastus medialis muscle were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, some saporin-injected rats were given implants containing testosterone or left untreated. Four weeks later, Motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. Compared to intact normal males, partial Motoneuron depletion resulted in decreased dendritic length in remaining quadriceps Motoneurons, and this atrophy was attenuated by testosterone treatment. To examine the functional consequences of the induced dendritic atrophy, and its attenuation with testosterone treatment, the activation of remaining quadriceps Motoneurons was assessed using peripheral nerve recording. Partial Motoneuron depletion resulted in decreased amplitudes of motor nerve activity, and these changes were attenuated by treatment with testosterone, providing a functional correlate to the neuroprotective effects of testosterone treatment on quadriceps Motoneuron morphology. Together, these findings suggest that testosterone has neuroprotective effects on morphology and function in both highly androgen-sensitive as well as more typical Motoneuron populations, further supporting a role for testosterone as a neurotherapeutic agent in the injured nervous system.
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Neuroprotective effect of testosterone treatment on Motoneuron recruitment following the death of nearby Motoneurons
Developmental neurobiology, 2009Co-Authors: Keith N. Fargo, Allison M. Foster, Dale R. SengelaubAbstract:Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have previously shown that Motoneuron death induces marked dendritic atrophy in surviving nearby Motoneurons. Additionally, in quadriceps Motoneurons, this atrophy is accompanied by decreases in motor nerve activity. However, treatment with testosterone partially attenuates changes in both the morphology and activation of quadriceps Motoneurons. Testosterone has an even larger neuroprotective effect on the morphology of Motoneurons of the spinal nucleus of the bulbocavernosus (SNB), in which testosterone treatment can completely prevent dendritic atrophy. The present experiment was performed to determine whether the greater neuroprotective effect of testosterone on SNB Motoneuron morphology was accompanied by a greater neuroprotective effect on motor activation. Right side SNB Motoneurons were killed by intramuscular injection of cholera toxin-conjugated saporin in adult male Sprague-Dawley rats. Animals were either given Silastic testosterone implants or left untreated. Four weeks later, left side SNB motor activation was assessed with peripheral nerve recording. The death of right side SNB Motoneurons resulted in several changes in the electrophysiological response properties of surviving left side SNB Motoneurons, including decreased background activity, increased response latency, increased activity duration, and decreased Motoneuron recruitment. Treatment with exogenous testosterone attenuated the increase in activity duration and completely prevented the decrease in Motoneuron recruitment. These data provide a functional correlate to the known protective effects of testosterone treatment on the morphology of these Motoneurons, and further support a role for testosterone as a therapeutic agent in the injured nervous system.
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Androgenic, but not estrogenic, protection of Motoneurons from somal and dendritic atrophy induced by the death of neighboring Motoneurons.
Developmental neurobiology, 2007Co-Authors: Keith N. Fargo, Dale R. SengelaubAbstract:Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have been investigating the effects of Motoneuron loss on surviving Motoneurons in a lumbar motor nucleus, the spinal nucleus of the bulbocavernosus (SNB). SNB Motoneurons undergo marked dendritic and somal atrophy following the experimentally induced death of other nearby SNB Motoneurons. However, treatment with testosterone at the time of lesioning attenuates this atrophy. Because testosterone can be metabolized into the estrogen estradiol (as well as other physiologically active steroid hormones), it was unknown whether the protective effect of testosterone was an androgen effect, an estrogen effect, or both. In the present experiment, we used a retrogradely transported neurotoxin to kill the majority of SNB Motoneurons on one side of the spinal cord only in adult male rats. Some animals were also treated with either testosterone, the androgen dihydrotestosterone (which cannot be converted into estradiol), or the estrogen estradiol. As seen previously, partial Motoneuron loss led to reductions in soma area and in dendritic length and extent in surviving Motoneurons. Testosterone and dihydrotestosterone attenuated these reductions, but estradiol had no protective effect. These results indicate that the neuroprotective effect of testosterone on the morphology of SNB Motoneurons following partial Motoneuron depletion is an androgen effect rather than an estrogen effect.
Kari Alitalo - One of the best experts on this subject based on the ideXlab platform.
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the parallel growth of Motoneuron axons with the dorsal aorta depends on vegfc vegfr3 signaling in zebrafish
Development, 2013Co-Authors: Hyoukbum Kwon, Tomonori Kashiwada, Kazuhide Asakawa, Shigetomo Fukuhara, Youngguen Kwon, Kari Alitalo, Koichi Kawakami, Masahiko Hibi, Koji Ando, Naoki MochizukiAbstract:Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary Motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these Motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the Motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in Motoneurons resulted in enhanced axon growth of Motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of Motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in Motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of Motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the Motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary Motoneurons.
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The parallel growth of Motoneuron axons with the dorsal aorta depends on Vegfc/Vegfr3 signaling in zebrafish
Development, 2013Co-Authors: Hyoukbum Kwon, Tomonori Kashiwada, Kazuhide Asakawa, Shigetomo Fukuhara, Youngguen Kwon, Koichi Kawakami, Masahiko Hibi, Koji Ando, Kari AlitaloAbstract:Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary Motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these Motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the Motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in Motoneurons resulted in enhanced axon growth of Motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of Motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in Motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of Motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the Motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary Motoneurons.
Hyoukbum Kwon - One of the best experts on this subject based on the ideXlab platform.
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the parallel growth of Motoneuron axons with the dorsal aorta depends on vegfc vegfr3 signaling in zebrafish
Development, 2013Co-Authors: Hyoukbum Kwon, Tomonori Kashiwada, Kazuhide Asakawa, Shigetomo Fukuhara, Youngguen Kwon, Kari Alitalo, Koichi Kawakami, Masahiko Hibi, Koji Ando, Naoki MochizukiAbstract:Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary Motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these Motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the Motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in Motoneurons resulted in enhanced axon growth of Motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of Motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in Motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of Motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the Motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary Motoneurons.
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The parallel growth of Motoneuron axons with the dorsal aorta depends on Vegfc/Vegfr3 signaling in zebrafish
Development, 2013Co-Authors: Hyoukbum Kwon, Tomonori Kashiwada, Kazuhide Asakawa, Shigetomo Fukuhara, Youngguen Kwon, Koichi Kawakami, Masahiko Hibi, Koji Ando, Kari AlitaloAbstract:Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary Motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these Motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the Motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in Motoneurons resulted in enhanced axon growth of Motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of Motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in Motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of Motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the Motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary Motoneurons.
Robert B. Darnell - One of the best experts on this subject based on the ideXlab platform.
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Cell type-specific CLIP reveals that NOVA regulates cytoskeleton interactions in Motoneurons
Genome Biology, 2018Co-Authors: Yuan Yuan, Shirley Xie, Jennifer C. Darnell, Andrew J. Darnell, Yuhki Saito, Hemali Phatnani, Elisabeth A. Murphy, Chaolin Zhang, Tom Maniatis, Robert B. DarnellAbstract:Background Alternative RNA processing plays an essential role in shaping cell identity and connectivity in the central nervous system. This is believed to involve differential regulation of RNA processing in various cell types. However, in vivo study of cell type-specific post-transcriptional regulation has been a challenge. Here, we describe a sensitive and stringent method combining genetics and CLIP (crosslinking and immunoprecipitation) to globally identify regulatory interactions between NOVA and RNA in the mouse spinal cord Motoneurons. Results We developed a means of undertaking Motoneuron-specific CLIP to explore Motoneuron-specific protein–RNA interactions relative to studies of the whole spinal cord in mouse. This allowed us to pinpoint differential RNA regulation specific to Motoneurons, revealing a major role for NOVA in regulating cytoskeleton interactions in Motoneurons. In particular, NOVA specifically promotes the palmitoylated isoform of the cytoskeleton protein Septin 8 in Motoneurons, which enhances dendritic arborization. Conclusions Our study demonstrates that cell type-specific RNA regulation is important for fine tuning Motoneuron physiology and highlights the value of defining RNA processing regulation at single cell type resolution.
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cell type specific clip reveals that nova regulates cytoskeleton interactions in Motoneurons
Genome Biology, 2018Co-Authors: Yuan Yuan, Jennifer C. Darnell, Andrew J. Darnell, Yuhki Saito, Hemali Phatnani, Elisabeth A. Murphy, Chaolin Zhang, Tom Maniatis, Robert B. DarnellAbstract:Alternative RNA processing plays an essential role in shaping cell identity and connectivity in the central nervous system. This is believed to involve differential regulation of RNA processing in various cell types. However, in vivo study of cell type-specific post-transcriptional regulation has been a challenge. Here, we describe a sensitive and stringent method combining genetics and CLIP (crosslinking and immunoprecipitation) to globally identify regulatory interactions between NOVA and RNA in the mouse spinal cord Motoneurons. We developed a means of undertaking Motoneuron-specific CLIP to explore Motoneuron-specific protein–RNA interactions relative to studies of the whole spinal cord in mouse. This allowed us to pinpoint differential RNA regulation specific to Motoneurons, revealing a major role for NOVA in regulating cytoskeleton interactions in Motoneurons. In particular, NOVA specifically promotes the palmitoylated isoform of the cytoskeleton protein Septin 8 in Motoneurons, which enhances dendritic arborization. Our study demonstrates that cell type-specific RNA regulation is important for fine tuning Motoneuron physiology and highlights the value of defining RNA processing regulation at single cell type resolution.
Naoki Mochizuki - One of the best experts on this subject based on the ideXlab platform.
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the parallel growth of Motoneuron axons with the dorsal aorta depends on vegfc vegfr3 signaling in zebrafish
Development, 2013Co-Authors: Hyoukbum Kwon, Tomonori Kashiwada, Kazuhide Asakawa, Shigetomo Fukuhara, Youngguen Kwon, Kari Alitalo, Koichi Kawakami, Masahiko Hibi, Koji Ando, Naoki MochizukiAbstract:Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary Motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these Motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the Motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in Motoneurons resulted in enhanced axon growth of Motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of Motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in Motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of Motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the Motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary Motoneurons.
