A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain.
Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured in fragile X syndrome, but the mechanisms that regulate mGluR-LTD remain incompletely understood. We report that conditional knockout of Cdh1, the key regulatory subunit of the ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC), profoundly impairs mGluR-LTD in the hippocampus. Mechanistically, we find that Cdh1-APC operates in the cytoplasm to drive mGluR-LTD. We also identify the fragile X syndrome protein FMRP as a substrate of Cdh1-APC. Endogenous Cdh1-APC forms a complex with endogenous FMRP, and knockout of Cdh1 impairs mGluR-induced ubiquitination and degradation of FMRP in the hippocampus. Knockout of FMRP suppresses, and expression of an FMRP mutant protein that fails to interact with Cdh1 phenocopies, the Cdh1 knockout phenotype of impaired mGluR-LTD. These findings define Cdh1-APC and FMRP as components of a novel ubiquitin signaling pathway that regulates mGluR-LTD in the brain.
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Ju
J
Huang
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Yoshiho
Y
Ikeuchi
Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Marcos
M
Malumbres
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bonni@wustl.edu.
Azad
A
Bonni
D000818:Animals; D000831:Animals, Newborn; D000841:Anisomycin / Q000494:pharmacology; D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D008822:Mice, Transgenic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
D000841:Anisomycin; D064200:Cdh1 Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D011500:Protein Synthesis Inhibitors; D018094:Receptors, Metabotropic Glutamate; D025801:Ubiquitin; C497684:Fmr1 protein, mouse; C577585:Fzr1 protein, mouse; C010117:3,4-dihydroxyphenylglycol