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.
Pubmed ID: 19217427 RIS Download
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A freely accessible on-line systems biology resource devoted to all aspects of protein modification, as well as other post-translational modifications. It provides valuable and unique tools for both cell biologists and mass spectroscopists. PhosphoSite is a human- and mouse-centric database. It includes features such as: viewing the locations of modified residues on molecular models; browsing and searching MS2 records by disease, tissue, and cell line; submitting lists of peptides to identify previously reported genes; searching by sub-cellular localization, treatment, tissues, cell types, cell lines and diseases, and protein types and protein domains; searching for experimentally-verified kinase substrates and viewing preferred substrate motifs; and viewing MS2 spectra for peptides and sites not previously published.
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