Mcl-1 is a key regulator of apoptosis in neural precursor cells and autophagy in post-mitotic neurons

Abstract

Unregulated neuronal cell death has been implicated in the pathogenesis of several neurological disorders and in acute neuronal injury such as stroke. Mcl-1, an anti-apoptotic member of the Bcl-2 family, is a known survival factor for hematopoietic cells, however little is known regarding its function in the nervous system. In this study, we examined the role of Mcl-1 in regulation of programmed cell death throughout nervous system development and in maintaining mature neurons. We found that both Nestin: Cre Mcl-1 and Foxg1: Cre Mcl-1 conditional knockout mice were embryonic lethal. Morphological analysis and immunohistochemical staining revealed severe deterioration of the cortices and an apoptotic phenotype, suggesting that Mcl-1 is required for embryonic neuronal survival. Both neural progenitors and newly differentiated neurons were affected, revealing that neurons were dying throughout the process of differentiation. Deletion of Mcl-1 in post mitotic neurons in postnatal mice with CamKIIalpha Cre also resulted in premature lethality. Cresyl Violet staining and NeuN immunohistochemistry revealed a rapid loss of neurons in the cortices of mutants. Electron micrographic imaging revealed double membraned vesicles within the cortical neurons, suggestive of an autophagic form of cell death. Consistent with this hypothesis, an upregulation of LC3 was observed in primary cortical neurons deficient for Mcl-1. Altogether our findings demonstrate that the loss of Mcl-1 in embryonic and post-mitotic neurons results in cell death. The two distinct forms of cell death activated indicate that Mcl-1 functions in multiple pathways to promote neuronal survival. In summary, we demonstrate that Mcl-1 is vital for the survival of neurons.