Cell-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus

J Neurosci. 2012 Aug 29;32(35):12051-65. doi: 10.1523/JNEUROSCI.1857-12.2012.

Abstract

Adult hippocampal neurogenesis is thought to be essential for learning and memory, and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of Disabled-1, an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain-of-function and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus, and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders.

Publication types

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

MeSH terms

  • Age Factors
  • Aging / genetics
  • Animals
  • Cell Adhesion Molecules, Neuronal / antagonists & inhibitors*
  • Cell Adhesion Molecules, Neuronal / physiology
  • Cell Line
  • Cells, Cultured
  • Extracellular Matrix Proteins / antagonists & inhibitors*
  • Extracellular Matrix Proteins / physiology
  • Gene Silencing / physiology
  • Hippocampus / cytology*
  • Hippocampus / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / physiology
  • Neurogenesis / genetics*
  • Rats
  • Rats, Sprague-Dawley
  • Reelin Protein
  • Serine Endopeptidases / physiology
  • Signal Transduction / genetics*

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Reelin Protein
  • Reln protein, rat
  • RELN protein, human
  • Reln protein, mouse
  • Serine Endopeptidases