The neuronal transcription factor MEIS2 is a calpain2 protease target.

Tight control over transcription factor activity is necessary for a sensible balance between cellular proliferation and differentiation in the embryo and during tissue homeostasis by adult stem cells, but mechanistic details have remained incomplete. The homeodomain transcription factor MEIS2 is an important regulator of neurogenesis in the ventricular-subventricular zone (V-SVZ) adult stem cell niche in mice. We here identify MEIS2 as direct target of the intracellular protease calpain2. Phosphorylation at conserved serine / threonine residues or dimerization with PBX1 reduced the sensitivity of MEIS2 towards cleavage by calpain2. In the adult V-SVZ, calpain2 activity is high in stem- and progenitor cells, but rapidly declines during neuronal differentiation, which is accompanied by increased stability of MEIS2 full-length protein. In accordance with this, blocking calpain2 activity in stem- and progenitor cells or overexpression of a cleavage-insensitive form of MEIS2 increased the production of neurons, while overexpression of a catalytically active CAPN2 reduced it. Collectively, our results support a key role for calpain2 in controlling the output of adult V-SVZ neural stem- and progenitor cells through cleavage of the neuronal fate determinant MEIS2.