γ-protocadherins Control Cortical Dendrite Arborization by Regulating the Activity of a FAK/PKC/MARCKS Signaling Pathway

Neuron. 2012 Apr 26;74(2):269-76. doi: 10.1016/j.neuron.2012.01.028.

Abstract

The 22 γ-protocadherins (γ-Pcdhs) potentially specify thousands of distinct homophilic adhesive interactions in the brain. Neonatal lethality of mice lacking the Pcdh-γ gene cluster has, however, precluded analysis of many brain regions. Here, we use a conditional Pcdh-γ allele to restrict mutation to the cerebral cortex and find that, in contrast to other central nervous system phenotypes, loss of γ-Pcdhs in cortical neurons does not affect their survival or result in reduced synaptic density. Instead, mutant cortical neurons exhibit severely reduced dendritic arborization. Mutant cortices have aberrantly high levels of protein kinase C (PKC) activity and of phosphorylated (inactive) myristoylated alanine-rich C-kinase substrate, a PKC target that promotes arborization. Dendrite complexity can be rescued in Pcdh-γ mutant neurons by inhibiting PKC, its upstream activator phospholipase C, or the γ-Pcdh binding partner focal adhesion kinase. Our results reveal a distinct role for the γ-Pcdhs in cortical development and identify a signaling pathway through which they play this role.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / abnormalities
  • Cerebral Cortex / cytology*
  • Dendrites / genetics*
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Expression Regulation, Developmental / genetics*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Neurons / cytology*
  • Protein Kinase C / metabolism
  • Sequence Deletion / genetics
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection / methods

Substances

  • Bacterial Proteins
  • Cadherins
  • Gamma-protocadherins
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • Marcks protein, mouse
  • Membrane Proteins
  • Transcription Factors
  • empty spiracles homeobox proteins
  • yellow fluorescent protein, Bacteria
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse
  • Protein Kinase C