Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells

Eric R. Bray, Benjamin J. Yungher, Konstantin Levay, Marcio Ribeiro, Gennady Dvoryanchikov, A. C. Ayupe, Kinjal Thakor, Victoria Marks, Michael Randolph, Matt C. Danzi, Tiffany M. Schmidt, Nirupa Chaudhari, Vance Lemmon, S. Hattar, Kevin Park

Research output: Contribution to journalArticle

Abstract

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 photosensitive 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. Here, Bray et al. used a variety of transgenic mice to demonstrate high survival and regenerative ability of one neuronal type in the retina and show several factors within these neurons, including thrombospondin-1 and syndecan-1 that confer high regenerative capacity.

Original languageEnglish (US)
Pages (from-to)642-657.e7
JournalNeuron
Volume103
Issue number4
DOIs
StatePublished - Aug 21 2019

Fingerprint

Thrombospondin 1
Retinal Ganglion Cells
Axons
Regeneration
Syndecan-1
Transgenic Mice
Genes
RNA Sequence Analysis
Wounds and Injuries
Retina
Carrier Proteins
Cell Death
Neurons

Keywords

  • axon growth
  • axon injury
  • axon regeneration
  • extracellular matrix protein
  • ipRGCs
  • melanopsin
  • retina
  • retinal ganglion cells
  • syndecan
  • thrombospondin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Bray, E. R., Yungher, B. J., Levay, K., Ribeiro, M., Dvoryanchikov, G., Ayupe, A. C., ... Park, K. (2019). Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells. Neuron, 103(4), 642-657.e7. https://doi.org/10.1016/j.neuron.2019.05.044

Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells. / Bray, Eric R.; Yungher, Benjamin J.; Levay, Konstantin; Ribeiro, Marcio; Dvoryanchikov, Gennady; Ayupe, A. C.; Thakor, Kinjal; Marks, Victoria; Randolph, Michael; Danzi, Matt C.; Schmidt, Tiffany M.; Chaudhari, Nirupa; Lemmon, Vance; Hattar, S.; Park, Kevin.

In: Neuron, Vol. 103, No. 4, 21.08.2019, p. 642-657.e7.

Research output: Contribution to journalArticle

Bray, ER, Yungher, BJ, Levay, K, Ribeiro, M, Dvoryanchikov, G, Ayupe, AC, Thakor, K, Marks, V, Randolph, M, Danzi, MC, Schmidt, TM, Chaudhari, N, Lemmon, V, Hattar, S & Park, K 2019, 'Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells', Neuron, vol. 103, no. 4, pp. 642-657.e7. https://doi.org/10.1016/j.neuron.2019.05.044
Bray ER, Yungher BJ, Levay K, Ribeiro M, Dvoryanchikov G, Ayupe AC et al. Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells. Neuron. 2019 Aug 21;103(4):642-657.e7. https://doi.org/10.1016/j.neuron.2019.05.044
Bray, Eric R. ; Yungher, Benjamin J. ; Levay, Konstantin ; Ribeiro, Marcio ; Dvoryanchikov, Gennady ; Ayupe, A. C. ; Thakor, Kinjal ; Marks, Victoria ; Randolph, Michael ; Danzi, Matt C. ; Schmidt, Tiffany M. ; Chaudhari, Nirupa ; Lemmon, Vance ; Hattar, S. ; Park, Kevin. / Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells. In: Neuron. 2019 ; Vol. 103, No. 4. pp. 642-657.e7.
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AU - Randolph, Michael

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