1. Academic Validation
  2. ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b

ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b

  • Cell Death Dis. 2019 May 1;10(5):360. doi: 10.1038/s41419-019-1596-z.
Keming Zhang 1 Qinbin Zhang 1 Jing Deng 2 Jinfang Li 1 Jiani Li 1 Lan Wen 3 Jingxi Ma 2 Changqing Li 4
Affiliations

Affiliations

  • 1 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of Neurology, Chongqing General Hospital, Chongqing, China.
  • 3 Department of Neurology, The Southwest Hospital, Chongqing, China.
  • 4 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Licq@hospital.cqmu.edu.cn.
Abstract

Transforming growth factor β (TGF-β) serves critical functions in brain injury, especially in cerebral ischemia; however, apart from its neuroprotective effects, its role in regulating neurogenesis is unclear. TGF-β acts in different ways; the most important, canonical TGF-β activity involves TGF-β Receptor I (TβRI) or the activin receptor-like kinase 5 (ALK5) signaling pathway. ALK5 signaling is a major determinant of adult neurogenesis. In our previous studies, growth arrest and DNA damage protein 45b (Gadd45b) mediated axonal plasticity after stroke. Here, we hypothesized that ALK5 signaling regulates neural plasticity and neurological function recovery after cerebral ischemia/reperfusion (I/R) via Gadd45b. First, ALK5 expression was significantly increased in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Then, we knocked down or overexpressed ALK5 with lentivirus (LV) in vivo. ALK5 knockdown reduced axonal and dendritic plasticity, with a concomitant decrease in neurological function recovery. Conversely, ALK5 overexpression significantly increased neurogenesis as well as functional recovery. Furthermore, ALK5 mediated Gadd45b protein levels by regulating SMAD2/3 phosphorylation. Finally, ALK5 coimmunoprecipitated with Gadd45b. Our results suggested that the ALK5 signaling pathway plays a critical role in mediating neural plasticity and neurological function recovery via Gadd45b after cerebral ischemia, representing a new potential target for cerebral I/R injury.

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