Depletion of SMN protein in mesenchymal progenitors impairs the development of bone and neuromuscular junction in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the deficiency of the survival motor neuron (SMN) protein, which leads to motor neuron dysfunction and muscle atrophy. In addition to the requirement for SMN in motor neurons, recent studies suggest that SMN deficiency in per...

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Published ineLife Vol. 12
Main Authors Sang-Hyeon, Hann, Seon-Yong, Kim, Kim, Ye Lynne, Young-Woo, Jo, Jong-Seol, Kang, Park Hyerim, Se-Young, Choi, Young-Yun, Kong
Format Journal Article
LanguageEnglish
Published Cambridge eLife Sciences Publications Ltd 06.02.2024
eLife Sciences Publications, Ltd
Subjects
Animal models
Atrophy
Bones
Cartilage
chondrocyte
Chondrocytes
fibro-adipogenic progenitor
Genes
Growth plate
Homeostasis
IGF signaling
Insulin-like growth factors
Liver
Medicine
Mesenchyme
Mineralization
Motor neurons
Neuromuscular diseases
neuromuscular junction
Neuromuscular junctions
Neuroscience
Pathogenesis
Pathology
Progenitor cells
Proteins
SMN protein
Spinal muscular atrophy
Transplantation
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Summary:Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the deficiency of the survival motor neuron (SMN) protein, which leads to motor neuron dysfunction and muscle atrophy. In addition to the requirement for SMN in motor neurons, recent studies suggest that SMN deficiency in peripheral tissues plays a key role in the pathogenesis of SMA. Using limb mesenchymal progenitor cell (MPC)-specific SMN-depleted mouse models, we reveal that SMN reduction in limb MPCs causes defects in the development of bone and neuromuscular junction (NMJ). Specifically, these mice exhibited impaired growth plate homeostasis and reduced insulin-like growth factor (IGF) signaling from chondrocytes, rather than from the liver. Furthermore, the reduction of SMN in fibro-adipogenic progenitors (FAPs) resulted in abnormal NMJ maturation, altered release of neurotransmitters, and NMJ morphological defects. Transplantation of healthy FAPs rescued the morphological deterioration. Our findings highlight the significance of mesenchymal SMN in neuromusculoskeletal pathogenesis of SMA and provide insights into potential therapeutic strategies targeting mesenchymal cells for the treatment of SMA.
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These authors contributed equally to this work.
ISSN:2050-084X
DOI:10.7554/eLife.92731