Calpains are a family of Ca2+-dependent cysteine proteases, and a number of calpain cleavage products have been associated with various neuronal processes, including differentiation. However, little is known about the mechanistic underpinnings of calpains in this context. Now, in this study (Müller et al., 2024), Dorothea Schulte and colleagues investigate the role of calpain-2 in the ventricular sub-ventricular zone (V-SVZ), a neurogenic stem cell niche in the brain of adult mice, where calpain-2 is known to regulate neuronal differentiation. Here, the authors isolate neural stem cells and transit amplifying progenitors from the V-SVZ and generate three-dimensional aggregates known as adult neurospheres (aNS), where differentiation can be manipulated and tracked. Using this in vitro system, the authors identify myeloid ecotropic viral integration site 2 (MEIS2), a transcription factor important for neurogenesis, as a cleavage product of calpain-2. Interestingly, MEIS2 levels increase as the aNS differentiate, which aligns with their observations that calpain-2 activity decreases during this time. Furthermore, phosphorylation of MEIS2 regulates its sensitivity to cleavage by calpain-2, and dimerisation of MEIS2 with another transcription factor, PBX1, also attenuates its cleavage. Thus, as well as uncovering how MEIS2 levels are regulated during differentiation of the V-SVZ, this study also highlights how the proteolytic cleavage of neuronal fate determinants can tune adult neurogenesis.
