Cux1 Enables Interhemispheric Connections of Layer II/III Neurons by Regulating Kv1-Dependent Firing

Neuron. 2016 Feb 3;89(3):494-506. doi: 10.1016/j.neuron.2015.12.020. Epub 2016 Jan 21.


Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function and connectivity. Activity-dependent mechanisms also contribute to wiring and circuit assembly, but whether and how they relate to TF-directed neuronal differentiation is poorly investigated. Here we demonstrate that the TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of Kv1 voltage-dependent potassium channels and the resulting postnatal switch to a Kv1-dependent firing mode. Loss of Cux1 function led to a decrease in the expression of Kv1 transcripts, aberrant firing responses, and selective loss of CC contralateral innervation. Firing and innervation were rescued by re-expression of Kv1 or postnatal reactivation of Cux1. Knocking down Kv1 mimicked Cux1-mediated CC axonal loss. These findings reveal that activity-dependent processes are central bona fide components of neuronal TF-differentiation programs and establish the importance of intrinsic firing modes in circuit assembly within the neocortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Animals
  • Corpus Callosum / cytology
  • Corpus Callosum / growth & development
  • Corpus Callosum / physiology
  • Gene Expression Regulation, Developmental*
  • Gene Knockdown Techniques
  • Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / physiology*
  • Nuclear Proteins / metabolism*
  • Primary Cell Culture
  • Repressor Proteins / metabolism*
  • Shaker Superfamily of Potassium Channels / biosynthesis
  • Shaker Superfamily of Potassium Channels / genetics
  • Shaker Superfamily of Potassium Channels / physiology*


  • Cux1 protein, mouse
  • Homeodomain Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Shaker Superfamily of Potassium Channels