Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury

Fatima M. Nathan, Yosuke Ohtake, Shuo Wang, Xinpei Jiang, Armin Sami, Hua Guo, Feng Quan Zhou, Shuxin Li

Research output: Contribution to journalArticlepeer-review

Abstract

Severed CNS axons fail to regenerate in adult mammals and there are no effective regenerative strategies to treat patients with CNS injuries. Several genes, including phosphatase and tensin homolog (PTEN) and Krüppel-like factors, regulate intrinsic growth capacity of mature neurons. The Lin28 gene is essential for cell development and pluripotency in worms and mammals. In this study, we evaluated the role of Lin28a in regulating regenerative capacity of diverse populations of CNS neurons in adult mammals. Using a neuron-specific Thy1 promoter, we generated transgenic mice that overexpress Lin28a protein in multiple populations of projection neurons, including corticospinal tracts and retinal ganglion cells. We demonstrate that upregulation of Lin28a in transgenic mice induces significant long distance regeneration of both corticospinal axons and the optic nerve in adult mice. Importantly, overexpression of Lin28a by post-injury treatment with adeno-associated virus type 2 (AAV2) vector stimulates dramatic regeneration of descending spinal tracts and optic nerve axons after lesions. Upregulation of Lin28a also enhances activity of the Akt signaling pathway in mature CNS neurons. Therefore, Lin28a is critical for regulating growth capacity of multiple CNS neurons and may become an important molecular target for treating CNS injuries.

Original languageEnglish (US)
Pages (from-to)1902-1917
Number of pages16
JournalMolecular Therapy
Volume28
Issue number8
DOIs
StatePublished - Aug 5 2020

Keywords

  • AAV vector
  • CNS lesion
  • Lin28
  • axon regeneration
  • gene delivery therapy
  • neuron growth capacity
  • optic nerve injury
  • spinal cord injury
  • transgenic mice

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury'. Together they form a unique fingerprint.

Cite this