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Amino Acid Sequence
Animals
COS Cells
Cell Adhesion/genetics/physiology
Cells, Cultured
Cercopithecus aethiops
Dendritic Spines/metabolism/pathology
Excitatory Postsynaptic Potentials/genetics/*physiology
Female
Glutamic Acid/metabolism
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins/genetics/*metabolism
Membrane Proteins/genetics/*metabolism
Mice
Molecular Sequence Data
Mutation
Nerve Tissue Proteins/genetics/*metabolism
Neurons/metabolism/*physiology
Phosphorylation
Protein-Serine-Threonine Kinases/genetics/*metabolism
Receptors, Cell Surface/genetics/*metabolism
Rett Syndrome/genetics/metabolism/pathology
Spine/metabolism/pathology
Synapses/genetics/*metabolism
Abstract:
Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans.