AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development.
AMP-activated protein kinase (AMPK) is an evolutionarily conserved metabolic sensor that responds to alterations in cellular energy levels to maintain energy balance. While its role in metabolic homeostasis is well documented, its role in mammalian development is less clear. Here we demonstrate that mutant mice lacking the regulatory AMPK beta1 subunit have profound brain abnormalities. The beta1(-/-) mice show atrophy of the dentate gyrus and cerebellum, and severe loss of neurons, oligodendrocytes, and myelination throughout the central nervous system. These abnormalities stem from reduced AMPK activity, with ensuing cell cycle defects in neural stem and progenitor cells (NPCs). The beta1(-/-) NPC deficits result from hypophosphorylation of the retinoblastoma protein (Rb), which is directly phosphorylated by AMPK at Ser(804). The AMPK-Rb axis is utilized by both growth factors and energy restriction to increase NPC growth. Our results reveal that AMPK integrates growth factor signaling with cell cycle control to regulate brain development.
Dasgupta
Biplab
B
Department of Pathology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Milbrandt
Jeffrey
J
D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
D016160:Retinoblastoma Protein; D055372:AMP-Activated Protein Kinases