ABSTRACT
Dendrite arbor structure is a critical determinant of nervous system function that must be actively maintained throughout life, but the signaling pathways that regulate dendrite maintenance are essentially unknown. We report that the Abelson (Abl) and Abl-related gene (Arg) nonreceptor tyrosine kinases are required for maintenance of cortical dendrites in the mouse brain. arg-/- cortical dendrites initially develop normally and are indistinguishable from wild-type dendrites at postnatal day 21. Dendrite branches are not efficiently maintained in arg-/- neurons, leading to a reduction in dendrite arbor size by early adulthood. More severe dendrite loss is observed in abl-/-arg-/- neurons. Elevation of Arg kinase activity in primary cortical neurons promotes axon and dendrite branching. Activation of integrin receptors by adhesion to laminin-1 or Semaphorin 7A also promotes neurite branching in cortical neurons, but this response is absent in arg-/- neurons because of the reduced dynamic behavior of mutant neurite branches. These data suggest that integrin signaling through Abl and Arg support cortical dendrite branch maintenance by promoting dendrite branch dynamics in response to adhesive cues.
Subject(s)
Dendrites/physiology , Integrins/physiology , Protein-Tyrosine Kinases/metabolism , Actins/metabolism , Animals , Base Sequence , Cerebral Cortex/enzymology , Cerebral Cortex/physiology , Cloning, Molecular , DNA Primers , Dendrites/enzymology , Mice , Mice, Inbred Strains , Mice, Knockout , Protein-Tyrosine Kinases/deficiency , Protein-Tyrosine Kinases/genetics , Restriction MappingABSTRACT
Abl family nonreceptor tyrosine kinases regulate cell morphogenesis through functional interactions with the actin cytoskeleton. The vertebrate Abl family kinases, Abl and Arg, are expressed in the adult mouse brain, where they may regulate actin cytoskeletal dynamics in mature neurons. Using immunoelectron microscopy, we have localized Abl and Arg to the pre- and postsynaptic compartments of synapses in the mouse hippocampal area CA1. Paired-pulse facilitation (PPF) was significantly reduced at the Schaffer collateral-CA1 (SC-CA1) excitatory synapses in hippocampal slices from abl-/- and arg-/- mice as compared with wild-type mice. Furthermore, treatment of wild-type slices with the specific Abl family kinase inhibitor STI571 also reduced PPF. Basal synaptic transmission, posttetanic potentiation (PTP), long-term potentiation (LTP), and long-term depression (LTD) were similar to wild-type controls in abl-/- and arg-/- slices and in STI571-treated wild-type slices. These results indicate that an important function of Abl and Arg is to modulate synaptic efficacy via a presynaptic mechanism during repetitive activation.
