Reappraisal of VAChT‐Cre: Preference in slow motor neurons innervating type I or IIa muscle fibers

Misawa, Hidemi; Inomata, Daijiro; Kikuchi, Miseri; Maruyama, Sae; Moriwaki, Yuji; Okuda, Takashi; Nukina, Nobuyuki; Yamanaka, Tatsuhiko

doi:10.1002/dvg.22979

Cited by 5 publications

(7 citation statements)

References 21 publications

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“…Then, we studied a cell autonomous role of Sp1–p11 in MN degeneration. In this context, most used MN-specific conditional knockouts mice target the subset of MNs that is mainly spared in the disease (VAChT:Cre model) 31–35 , or other cells types besides MNs (Hb9:Cre model) 36–38 , including spinal cord interneurons involved in rhythm generation during locomotor activity. Therefore, here we performed intraspinal microinjections of neuron-specific LVV-dnSp1 or LVV-shRNA p11 (see Fig.…”

Section: Resultsmentioning

confidence: 99%

Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1

et al. 2019

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Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11-TASK1 pathway is a potential target for treatment of degeneration of motor neurons.

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Section: Resultsmentioning

confidence: 99%

Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1

et al. 2019

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“…However, mating TFG f/+; Nestin-Cre with TFG f/f did not result in the birth of any TFG f/f; Nestin-Cre mice, suggesting neuronal TFG to be essential for embryonic development. To circumvent the lethality of deleting TFG during embryonic development, we utilized VAChT-Cre.Early mice, in which Cre expression is driven by the 11.3 kb human vesicular acetylcholine transporter (VAChT) promoter and starts approximately 7 days after birth 19 , 20 . In VAChT-Cre mice, Cre expression is restricted to a limited fraction of postnatal somatomotor neurons 19 , which were recently revealed to mainly be slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons 20 .…”

Section: Resultsmentioning

confidence: 99%

“…To circumvent the lethality of deleting TFG during embryonic development, we utilized VAChT-Cre.Early mice, in which Cre expression is driven by the 11.3 kb human vesicular acetylcholine transporter (VAChT) promoter and starts approximately 7 days after birth 19 , 20 . In VAChT-Cre mice, Cre expression is restricted to a limited fraction of postnatal somatomotor neurons 19 , which were recently revealed to mainly be slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons 20 . Hence, TFG f/f; VAChT-Cre.Early mice lack TFG predominantly in these subsets of motor neurons, rather than in motor neurons in general.…”

Section: Resultsmentioning

confidence: 99%

“…Motor neuron-specific TFG KO mice (MNTFG KO) were generated by crossing TFG floxed mice 18 with VAChT-Cre.Early mice 19 , 20 . Since VAChT-Cre mice were recently demonstrated to express Cre recombinase specifically in slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons 20 , but in neither fast-twitch fatigable (FF) nor γ-type motor neurons, we use the designation vMNTFG KO to describe TFG f/f; VAChT-Cre.Early mice herein. Muscle-specific TFG KO mice (MUSTFG KO) were generated by crossing TFG floxed mice with transgenic mice expressing Cre under a muscle-specific alpha-actin promoter provided by RIKEN BRC (MuCre-A mice, RBRC01386) 21 .…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study 18 , our group generated TFG floxed mice and reported the importance of TFG in the regulation of pancreatic β cell mass and functions. By crossing with VAChT-Cre.Early mice 19 , 20 , we generated postnatal motor neuron-specific TFG KO mice and report herein that deletion of TFG in the motor neuron results in denervation of neuromuscular junctions (NMJs) as well as muscle atrophy. Furthermore, we propose a possible contribution of muscle TFG, downregulated upon denervation or with aging, to the physiological maintenance of NMJs.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of neuronal and muscular Trk-fused gene (TFG) defects in the development of neurodegenerative diseases

Yamamotoya

Hasei

Akasaka

et al. 2022

Sci Rep

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Trk-fused gene (TFG) mutations have been identified in patients with several neurodegenerative diseases. In this study, we attempted to clarify the effects of TFG deletions in motor neurons and in muscle fibers, using tissue-specific TFG knockout (vMNTFG KO and MUSTFG KO) mice. vMNTFG KO, generated by crossing TFG floxed with VAChT-Cre, showed deterioration of motor function and muscle atrophy especially in slow-twitch soleus muscle, in line with the predominant Cre expression in slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons. Consistently, denervation of the neuromuscular junction (NMJ) was apparent in the soleus, but not in the extensor digitorum longus, muscle. Muscle TFG expressions were significantly downregulated in vMNTFG KO, presumably due to decreased muscle IGF-1 concentrations. However, interestingly, MUSTFG KO mice showed no apparent impairment of muscle movements, though a denervation marker, AChRγ, was elevated and Agrin-induced AChR clustering in C2C12 myotubes was inhibited. Our results clarify that loss of motor neuron TFG is sufficient for the occurrence of NMJ degeneration and muscle atrophy, though lack of muscle TFG may exert an additional effect. Reduced muscle TFG, also observed in aged mice, might be involved in age-related NMJ degeneration, and this issue merits further study.

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X‐Ray Fluoroscopy‐Based Kinematic Analysis of Quadrupedal Locomotion in Slow and Fast Fatigue‐Resistant Motor Neuron‐Deleted Mice

Ono,

Inomata,

Ohgaki

et al. 2024

Muscle and Nerve

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Introduction/AimsVAChT‐Cre is a transgenic mouse line targeting slow‐twitch fatigue‐resistant and fast‐twitch fatigue‐resistant motor neurons that innervate oxidative type I and type IIa muscle fibers. To ablate these neurons, VAChT‐Cre mice were crossbred with NSE‐DTA mice, leading to the expression of diphtheria toxin A after Cre‐mediated excision. The resulting VAChT‐Cre;NSE‐DTA mice exhibited motor deficits, abnormal locomotion, muscular atrophy, and tremor, making them a useful model for studying motor neuron physiology and pathology. In this study, we conducted a kinematic analysis to examine their abnormal locomotor phenotype.MethodsThe quadrupedal walking of VAChT‐Cre;NSE‐DTA and control mice along a 500 mm acrylic tunnel was analyzed using an X‐ray fluoroscopic system. Stride duration, stride length, footfall patterns, and limb and trunk kinematics were quantified and compared between the two groups.ResultsOur results demonstrated that VAChT‐Cre;NSE‐DTA mice walked more slowly than control mice (99.2 ± 43.5 mm/s vs. 120.5 ± 27.0 mm/s) and had a longer cycle duration (0.54 ± 0.19 s vs. 0.41 ± 0.09 s). In addition, the hindlimb was comparatively more flexed during the stance phase, the trunk was more rounded and humpbacked, and the cervix was lower in VAChT‐Cre;NSE‐DTA mice than in the control mice during locomotion.DiscussionThese characteristic differences in the gait kinematics might be attributed to a malfunctioning of the motor units with slow‐twitch fatigue‐resistant and fast‐twitch fatigue‐resistant types in VAChT‐Cre;NSE‐DTA mice. The basic description of the locomotor characteristics of this transgenic mouse line may serve as a basis for future comparative analyses.

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Reappraisal of VAChT‐Cre: Preference in slow motor neurons innervating type I or IIa muscle fibers

Cited by 5 publications

References 21 publications

Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1

Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1

Involvement of neuronal and muscular Trk-fused gene (TFG) defects in the development of neurodegenerative diseases

X‐Ray Fluoroscopy‐Based Kinematic Analysis of Quadrupedal Locomotion in Slow and Fast Fatigue‐Resistant Motor Neuron‐Deleted Mice

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