The role of Mcl-1 in developmental neurogenesis

Abstract

Neurogenesis is marked by cell cycle exit and differentiation of neural stem cells (NSCs) into post mitotic neurons. Mitochondrial morphology and function regulate neurogenesis through mediating a metabolic switch from glycolysis to oxidative phosphorylation (OXPHOS). Myeloid cell leukemia 1 (Mcl-1), a member of the B-cell lymphoma 2 family of proteins, is essential for survival of neural precursor cells (NPCs) during neurogenesis. Mcl-1 also regulates mitochondrial dynamics. Currently it remains elusive whether Mcl-1 maintains mitochondrial dynamics during neurogenesis. Therefore, my hypothesis is that Mcl-1 promotes survival of NPCs during neurogenesis through mediating mitochondrial dynamics. Conditional knockout mouse lines of Mcl-1 (MKO) were generated using the Cre/Lox system. The effect of Mcl-1 on cell cycle exit in the developing forebrain was determined through a BrdU/EdU pulse assay. Mitochondrial number and morphology in MKO embryos were examined in the medial ganglionic eminence (MGE) through immunohistochemistry (IHC) and electron microscopy (EM). Loss of Mcl-1 resulted in a significantly greater number of NPCs exiting the cell cycle at E11. IHC and EM analysis reveal that mitochondria were more numerous in MKO NPCs. The results of this study suggest that Mcl-1 serves additional roles in mitochondrial dynamics and cell cycle exit during neurogenesis, which may be essential for proper nervous system development.