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bioRxiv · 10.1101/2025.09.22.677817

Calpain-2 inhibition or deletion enhances levels of the transcription Factor, MEIS2, and stimulates neurogenesis

Baudry, M.·Reece, T.·Shahi, R.·Bi, X.
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Abstract

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. 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. Acute treatment of wild-type (WT) mice with NA-184 increased levels of MEIS2 in various brain structures. It also increased numbers of neurons immunopositive for Ki67 and DCX, two markers for neurogenesis, in both the SVZ and DG. MEIS2 levels were elevated in C2KO mouse brain, while they were decreased in C1KO mouse brain. Compared to those in WT mice, neurons from C2KO mice exhibited a decrease in the number of filipodia spines and an increase in the number of mushroom spines, while those from C1KO exhibited opposite changes. 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. 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/677817v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1277e38org.highwire.dtl.DTLVardef@1cfa4aaorg.highwire.dtl.DTLVardef@143ac65org.highwire.dtl.DTLVardef@1eb28de_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Baudry, M., Reece, T., Shahi, R., Bi, X.. 2025-09-25. Calpain-2 inhibition or deletion enhances levels of the transcription Factor, MEIS2, and stimulates neurogenesis. https://doi.org/10.1101/2025.09.22.677817

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