Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells

被引:96
作者
Bray, Eric R. [1 ]
Yungher, Benjamin J. [1 ]
Levay, Konstantin [1 ]
Ribeiro, Marcio [1 ]
Dvoryanchikov, Gennady [2 ]
Ayupe, Ana C. [1 ]
Thakor, Kinjal [1 ]
Marks, Victoria [1 ]
Randolph, Michael [1 ]
Danzi, Matt C. [1 ]
Schmidt, Tiffany M. [3 ]
Chaudhari, Nirupa [2 ]
Lemmon, Vance P. [1 ]
Hattar, Samer [4 ,5 ]
Park, Kevin K. [1 ]
机构
[1] Univ Miami, Dept Neurol Surg, Miami Project Cure Paralysis, Miller Sch Med, Miami, FL 33136 USA
[2] Univ Miami, Dept Physiol & Biophys, Dept Otolaryngol, Miller Sch Med, Miami, FL 33136 USA
[3] Northwestern Univ, Dept Neurobiol, Evanston, IL USA
[4] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA
[5] NIMH, John Edward Porter Neurosci Res Ctr, Bethesda, MD 20892 USA
关键词
OPTIC-NERVE; NEURITE OUTGROWTH; ADULT CNS; GROWTH; EXPRESSION; INJURY; MODULATION; SYNDECAN-1; SURVIVAL; ADHESION;
D O I
10.1016/j.neuron.2019.05.044
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Neuronal subtypes show diverse injury responses, but the molecular underpinnings remain elusive. Using transgenic mice that allow reliable visualization of axonal fate, we demonstrate that intrinsically photo-sensitive retinal ganglion cells (ipRGCs) are both resilient to cell death and highly regenerative. Using RNA sequencing (RNA-seq), we show genes that are differentially expressed in ipRGCs and that associate with their survival and axon regeneration. Strikingly, thrombospondin-1 (Thbs1) ranked as the most differentially expressed gene, along with the well-documented injury-response genes Atf3 and Jun. THBS1 knockdown in RGCs eliminated axon regeneration. Conversely, RGC overexpression of THBS1 enhanced regeneration in both ipRGCs and non-ipRGCs, an effect that was dependent on syndecan- 1, a known THBS1-binding protein. All structural domains of the THBS1 were not equally effective; the trimerization and C-terminal domains promoted regeneration, while the THBS type-1 repeats were dispensable. Our results identify cell-type-specific induction of Thbs1 as a novel gene conferring high regenerative capacity.
引用
收藏
页码:642 / +
页数:23
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