Abstract
Calpains are calcium regulated cysteine proteases that have been described in a wide range of cellular processes, including apoptosis, migration and cell cycle regulation. In addition, calpains have been implicated in differentiation, but their impact on neural differentiation requires further investigation. Here, we addressed the role of calpain 1 and calpain 2 in neural stem cell (NSC) self-renewal and differentiation. We found that calpain inhibition using either the chemical inhibitor calpeptin or the endogenous calpain inhibitor calpastatin favored differentiation of NSCs. This effect was associated with significant changes in cell cycle-related proteins and may be regulated by calcium. Interestingly, calpain 1 and calpain 2 were found to play distinct roles in NSC fate decision. Calpain 1 expression levels were higher in self-renewing NSC and decreased with differentiation, while calpain 2 increased throughout differentiation. In addition, calpain 1 silencing resulted in increased levels of both neuronal and glial markers, β-III Tubulin and glial fibrillary acidic protein (GFAP). Calpain 2 silencing elicited decreased levels of GFAP. These results support a role for calpain 1 in repressing differentiation, thus maintaining a proliferative NSC pool, and suggest that calpain 2 is involved in glial differentiation.
Highlights
Differentiation is the process by which stem cells give rise to committed and specialized cells [1]
Calpains have already been implicated in several differentiation systems [20,32,33,34], their involvement during neural differentiation has not yet been fully explored
We have previously shown that cysteine proteases, such as caspases, regulate mouse Neural stem cells (NSC) differentiation by interfering with the FOXO3A/Id1 signaling pathway [36]
Summary
Differentiation is the process by which stem cells give rise to committed and specialized cells [1]. The molecular pathways regulating differentiation of stem cells are still not fully defined, and may implicate cell cycle, apoptosis and migration, among other processes. Calpains are a large conserved family of cysteine proteases regulated by calcium which cleave many different substrates, modulating protein activity [7]. Calpains have been implicated in the regulation of a wide range of cellular processes, including cell cycle, migration, apoptosis, autophagy and synaptic plasticity [8,9,10,11,12,13,14]. Substrates cleaved by different calpains vary depending on the context, probably as a consequence of the complex regulatory network affecting these proteases. Calpain 1 and calpain 2 are the most studied and abundant calpain molecules in the brain [8]
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