Pax3 通过轴突侧枝表达 PSA-NCAM 诱导目标特异性神经再支配

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2023-12-12 DOI:10.1016/j.pneurobio.2023.102560
J. Sebastian Jara , Hasan X. Avci , Ioanna Kouremenou , Mohamed Doulazmi , Joelle Bakouche , Caroline Dubacq , Catherine Goyenvalle , Jean Mariani , Ann M. Lohof , Rachel M. Sherrard
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引用次数: 0

摘要

受损或功能障碍的神经回路可在病变后被未受损神经元的轴突萌发和侧枝生长所取代。遗憾的是,这些新的连接往往是无序的,很少能带来临床改善。在小鼠橄榄小脑路径中,脑源性神经营养因子(BDNF)可通过保留完整的下橄榄轴突(攀缘纤维)诱导正确靶向的病变后小脑神经再支配。在这项研究中,我们确定了BDNF诱导这种修复的细胞过程。向失去神经支配的小脑注射BDNF可使下橄榄神经元中的转录因子Pax3上调,并诱导爬行纤维快速萌发。Pax3反过来又会增加萌发的攀缘纤维路径中的多聚硅酸-神经细胞粘附分子(PSA-NCAM),促进侧支生长和寻路,以重新支配正确的目标--小脑浦肯野细胞。橄榄核Pax3过表达可重现BDNF诱导的神经再支配,而橄榄核Pax3敲除则可消除BDNF诱导的神经再支配,这表明Pax3通过上调PSA-NCAM促进轴突生长和引导,PSA-NCAM可能位于轴突的生长锥上。这些数据表明,将生长促进限制在潜在的再神经传入神经元上,而不是刺激整个神经回路或损伤部位,可促进轴突生长和适当的引导,从而准确地重建神经回路。
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Pax3 induces target-specific reinnervation through axon collateral expression of PSA-NCAM

Damaged or dysfunctional neural circuits can be replaced after a lesion by axon sprouting and collateral growth from undamaged neurons. Unfortunately, these new connections are often disorganized and rarely produce clinical improvement. Here we investigate how to promote post-lesion axonal collateral growth, while retaining correct cellular targeting. In the mouse olivocerebellar path, brain-derived neurotrophic factor (BDNF) induces correctly-targeted post-lesion cerebellar reinnervation by remaining intact inferior olivary axons (climbing fibers). In this study we identified cellular processes through which BDNF induces this repair. BDNF injection into the denervated cerebellum upregulates the transcription factor Pax3 in inferior olivary neurons and induces rapid climbing fiber sprouting. Pax3 in turn increases polysialic acid-neural cell adhesion molecule (PSA-NCAM) in the sprouting climbing fiber path, facilitating collateral outgrowth and pathfinding to reinnervate the correct targets, cerebellar Purkinje cells. BDNF-induced reinnervation can be reproduced by olivary Pax3 overexpression, and abolished by olivary Pax3 knockdown, suggesting that Pax3 promotes axon growth and guidance through upregulating PSA-NCAM, probably on the axon’s growth cone. These data indicate that restricting growth-promotion to potential reinnervating afferent neurons, as opposed to stimulating the whole circuit or the injury site, allows axon growth and appropriate guidance, thus accurately rebuilding a neural circuit.

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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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