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Calpain-2 Inhibition or Deletion Enhances Levels of the Transcription Factor, MEIS2, and Stimulates Neurogenesis
Michel Baudry1, Tristan Reece2, Roxana Shahi1
1CDM, Western University of Health Sciences, Pomona, CA 91766, USA.
Introduction:
Neurogenesis takes place in the subventricular zone (SVZ) and in the dentate gyrus (DG) of the hippocampus of many adult mammalian species. Recent findings indicate that calpain-2 could participate in neurogenesis regulation through the truncation of the transcription factor, Myeloid Ecotropic Viral Integration Site 2 (MEIS2). The present study aimed to test the effects of calpain-2 inhibition/deletion on MEIS2 levels and neurogenesis in adult mice.
Methods:
Two-to-three month-old mice were injected with a selective calpain-2 inhibitor, NA-184, and sacrificed 24 h later. In addition, two-to-three month-old conditional calpain-2 knock-out (C2KO) and calpain-1 knock-out (C1KO) mice were used. Levels of MEIS2 and of cell markers for neurogenesis were analyzed using immunohistochemistry and western blots. Dendritic spines in hippocampal neurons were also analyzed by Golgi staining.
Results:
Acute treatment of wild-type (WT) mice with NA-184 increased levels of MEIS2 in various brain structures. It also increased the number of neurons immunopositive for Ki67 and DCX, two markers for neurogenesis, in both the SVZ and DG. MEIS2 levels were elevated in the C2KO mouse brain, while they were decreased in the C1KO mouse brain. Compared to those in WT mice, neurons from C2KO mice exhibited a decrease in the number of filopodia spines and an increase in the number of mushroom spines, while those from C1KO exhibited opposite changes.
Discussion:
These findings further emphasize the critical and opposite roles of calpain-1 and calpain-2 in brain functions in general, and in neurogenesis in particular, with MEIS2 as a major downstream mediator. These findings also underline previous conclusions that calpain-1 promotes spine maturation and synaptic plasticity while calpain-2 hinders spine maturation and synaptic plasticity.
Conclusion:
These results indicate that calpain-2 inhibition/deletion results in increased neurogenesis, as well as in increased maturation of dendritic spines, potentially due to increased levels and activation of MEIS2.
Insights
Inhibiting calpain-2 in adult mice boosts neurogenesis and dendritic spine maturation by increasing Myeloid Ecotropic Viral Integration Site 2 (MEIS2) levels. Calpain-1 plays an opposing role in these processes.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Adult mammalian neurogenesis occurs in the subventricular zone (SVZ) and dentate gyrus (DG).
- Calpain-2 may regulate neurogenesis by truncating the transcription factor Myeloid Ecotropic Viral Integration Site 2 (MEIS2).
Purpose of the Study:
- To investigate the effects of calpain-2 inhibition or deletion on MEIS2 levels and neurogenesis in adult mice.
- To elucidate the opposing roles of calpain-1 and calpain-2 in neurogenesis and synaptic plasticity.
Main Methods:
- Adult mice were treated with a calpain-2 inhibitor (NA-184) or were conditional knock-outs for calpain-2 (C2KO) or calpain-1 (C1KO).
- Neurogenesis markers (Ki67, DCX) and MEIS2 levels were assessed via immunohistochemistry and western blots.
- Dendritic spine morphology was analyzed using Golgi staining.
Main Results:
- NA-184 treatment and C2KO increased MEIS2 levels and neurogenesis markers in the SVZ and DG.
- C2KO mice showed altered dendritic spine maturation (fewer filopodia, more mushroom spines) compared to wild-type.
- Calpain-1 deficiency (C1KO) led to decreased MEIS2 levels and opposite changes in dendritic spine morphology.
Conclusions:
- Calpain-2 inhibition/deletion enhances neurogenesis and dendritic spine maturation, mediated by increased MEIS2 levels.
- Calpain-1 and calpain-2 exhibit critical and opposing roles in brain function, particularly in neurogenesis and synaptic plasticity.
- Calpain-2 hinders, while calpain-1 promotes, spine maturation and synaptic plasticity.
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