Npas4 regulates Mdm2 and thus Dcx in experience-dependent dendritic spine development of newborn olfactory bulb interneurons

Cell Rep. 2014 Aug 7;8(3):843-57. doi: 10.1016/j.celrep.2014.06.056. Epub 2014 Jul 31.

Abstract

Sensory experience regulates the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB). Little is known about how sensory experience regulates the dendritic spine development of OB interneurons, such as granule cells (GCs), although it is well studied in mitral/tufted cells. Here, we identify a transcription factor, Npas4, which is expressed in OB GCs immediately after sensory input and is required for dendritic spine formation. Npas4 overexpression in OB GCs increases dendritic spine density, even under sensory deprivation, and rescues reduction of dendrite spine density in the Npas4 knockout OB. Furthermore, loss of Npas4 upregulates expression of the E3-ubiquitin ligase Mdm2, which ubiquitinates a microtubule-associated protein Dcx. This leads to reduction in the dendritic spine density of OB GCs. Together, these findings suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade Dcx during dendritic spine development in newborn OB GCs after sensory experience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Dendritic Spines / metabolism*
  • Dendritic Spines / physiology
  • Interneurons / metabolism*
  • Interneurons / physiology
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Neurogenesis
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Olfactory Bulb / cytology
  • Olfactory Bulb / growth & development
  • Olfactory Bulb / metabolism*
  • Olfactory Bulb / physiology
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Smell
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Microtubule-Associated Proteins
  • Neuropeptides
  • Npas4 protein, mouse
  • doublecortin protein
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2