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IRES-mediated Wnt2 translation in apoptotic neurons triggers astrocyte dedifferentiation

Hong Fan1,2, Jialei Yang1,3, Kun Zhang1

  • 1Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an, Shaanxi, 710032, China.

NPJ Regenerative Medicine
|September 2, 2022
PubMed

Insights

Apoptotic neurons activate Wnt signaling, promoting astrocyte dedifferentiation and neurogenesis after brain injury. This apoptosis-initiated Wnt pathway is crucial for neuronal regeneration and functional recovery.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Regenerative Medicine

Background:

  • Reactive astrogliosis exhibits neural progenitor properties, but the trigger for astrocyte dedifferentiation post-injury is unknown.
  • Understanding astrocyte response to injury is key for developing regenerative strategies.

Purpose of the Study:

  • To elucidate the mechanism by which brain injury induces astrocyte dedifferentiation.
  • To investigate the role of Wnt signaling and apoptosis in neuronal regeneration.

Main Methods:

  • Investigated Wnt2 protein expression in apoptotic neurons and Wnt signaling in reactive astrocytes in mouse, primate, and human ischemic models.
  • Utilized Wnt2 shRNA, Wnt2 overexpression, and caspase-3 knockout models.
  • Examined the role of internal ribosome entry site (IRES)-mediated translation and death associated protein 5 (DAP5) in Wnt2 upregulation.

Main Results:

  • Ischemia rapidly upregulates Wnt2 in apoptotic neurons, activating Wnt signaling in reactive astrocytes.
  • Wnt2 inhibition prevents astrocyte dedifferentiation; Wnt2 overexpression promotes progenitor markers and neurogenesis.
  • Apoptotic neurons upregulate Wnt2 via IRES-mediated translation involving DAP5, triggering astrocyte dedifferentiation and facilitating neurogenesis and functional recovery.

Conclusions:

  • Demonstrated an apoptosis-initiated Wnt-activating mechanism driving astrocyte dedifferentiation.
  • This pathway is critical for neuronal regeneration and functional recovery following ischemic injury.
  • Targeting this mechanism holds therapeutic potential for brain repair.

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