Motor defects in a Drosophila model for spinal muscular atrophy result from SMN depletion during early neurogenesis

doi:10.1371/journal.pgen.1010325

	Motor defects in a Drosophila model for spinal muscular atrophy result from SMN depletion during early neurogenesis
	Grice, Stuart J.1; Liu, Ji-Long1,2
	2022-07-01
发表期刊	PLOS GENETICS (IF:4.0[JCR-2023],4.9[5-Year])
ISSN	1553-7404
卷号	18 期号:7
发表状态	已发表
DOI	10.1371/journal.pgen.1010325
摘要	["Author summarySpinal muscular atrophy (SMA) is the most common genetic cause of infant mortality and leads to the degeneration of the nerves that control muscle function. Loss-of-function mutations in the widely expressed survival motor neuron 1 (SMN1) gene cause SMA, but how low levels of SMN protein cause the neuronal dysfunction is not known. Although SMA is a disease of nerve degeneration, SMN function during nerve cell development may be important, particularly in severe forms of SMA. Nevertheless, how the defects during development and throughout early life contribute to the disease is not well understood. We have previously demonstrated that SMN protein becomes enriched in neuroblasts, which are the cells that divide to produce neurons. In the present study, motor defects observed in our fly model for SMA could be rescued by restoring SMN in neuroblasts alone. In addition, we show that knocking down SMN in healthy flies within the same cell type causes impaired motor function. The present study shows that the manipulation of SMN in a developmentally important cell type can cause motor defects, indicating that a period of abnormal neurodevelopment may contribute to SMA.","Spinal muscular atrophy (SMA) is the most common autosomal recessive neurodegenerative disease, and is characterised by spinal motor neuron loss, impaired motor function and, often, premature death. Mutations and deletions in the widely expressed survival motor neuron 1 (SMN1) gene cause SMA; however, the mechanisms underlying the selectivity of motor neuron degeneration are not well understood. Although SMA is degenerative in nature, SMN function during embryonic and early postnatal development appears to be essential for motor neuron survival in animal models and humans. Notwithstanding, how developmental defects contribute to the subversion of postnatal and adult motor function remains elusive. Here, in a Drosophila SMA model, we show that neurodevelopmental defects precede gross locomotor dysfunction in larvae. Furthermore, to specifically address the relevance of SMN during neurogenesis and in neurogenic cell types, we show that SMN knockdown using neuroblast-specific and pan-neuronal drivers, but not differentiated neuron or glial cell drivers, impairs adult motor function. Using targeted knockdown, we further restricted SMN manipulation in neuroblasts to a defined time window. Our aim was to express specifically in the neuronal progenitor cell types that have not formed synapses, and thus a time that precedes neuromuscular junction formation and maturation. By restoring SMN levels in these distinct neuronal population, we partially rescue the larval locomotor defects of Smn mutants. Finally, combinatorial SMN knockdown in immature and mature neurons synergistically enhances the locomotor and survival phenotypes. Our in-vivo study is the first to directly rescue the motor defects of an SMA model by expressing Smn in an identifiable population of Drosophila neuroblasts and developing neurons, highlighting that neuronal sensitivity to SMN loss may arise before synapse establishment and nerve cell maturation."]
URL	查看原文
收录类别	SCI
语种	英语
WOS研究方向	Genetics & Heredity
WOS类目	Genetics & Heredity
WOS记录号	WOS:000975526000001
出版者	PUBLIC LIBRARY SCIENCE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/299826
专题	生命科学与技术学院生命科学与技术学院_PI研究组_刘冀珑组
通讯作者	Grice, Stuart J.; Liu, Ji-Long
作者单位	1.Univ Oxford, Med Res Council Funct Genom Unit, Dept Physiol Anat & Genet, Oxford, England 2.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Grice, Stuart J.,Liu, Ji-Long. Motor defects in a Drosophila model for spinal muscular atrophy result from SMN depletion during early neurogenesis[J]. PLOS GENETICS,2022,18(7).
APA	Grice, Stuart J.,&Liu, Ji-Long.(2022).Motor defects in a Drosophila model for spinal muscular atrophy result from SMN depletion during early neurogenesis.PLOS GENETICS,18(7).
MLA	Grice, Stuart J.,et al."Motor defects in a Drosophila model for spinal muscular atrophy result from SMN depletion during early neurogenesis".PLOS GENETICS 18.7(2022).