VLDLR is not essential for reelin-induced neuronal aggregation but suppresses neuronal invasion into the marginal zone

Development. 2020 Jun 15;147(12):dev189936. doi: 10.1242/dev.189936.


In the developing neocortex, radially migrating neurons stop migration and form layers beneath the marginal zone (MZ). Reelin plays essential roles in these processes via its receptors, apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR). Although we recently reported that reelin causes neuronal aggregation via ApoER2, which is thought to be important for the subsequent layer formation, it remains unknown what effect reelin exerts via the VLDLR. Here, we found that ectopic reelin overexpression in the Vldlr-mutant mouse cortex causes neuronal aggregation, but without an MZ-like cell-sparse central region that is formed when reelin is overexpressed in the normal cortex. We also found that both the early-born and late-born Vldlr-deficient neurons invade the MZ and exhibit impaired dendrite outgrowth from before birth. Rescue experiments indicate that VLDLR suppresses neuronal invasion into the MZ via a cell-autonomous mechanism, possibly mediated by Rap1, integrin and Akt. These results suggest that VLDLR is not a prerequisite for reelin-induced neuronal aggregation and that the major role of VLDLR is to suppress neuronal invasion into the MZ during neocortical development.

Keywords: Marginal zone; Mouse; Neocortex; Neuronal aggregation; Reelin; VLDLR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cerebral Cortex / metabolism
  • Dendrites / metabolism
  • Embryo, Mammalian / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Integrin alpha5 / metabolism
  • LDL-Receptor Related Proteins / deficiency
  • LDL-Receptor Related Proteins / genetics
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyramidal Cells / metabolism
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Reelin Protein
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • rap1 GTP-Binding Proteins / metabolism


  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Integrin alpha5
  • LDL-Receptor Related Proteins
  • Nerve Tissue Proteins
  • Receptors, LDL
  • Reelin Protein
  • VLDL receptor
  • low density lipoprotein receptor-related protein 8
  • Proto-Oncogene Proteins c-akt
  • Reln protein, mouse
  • Serine Endopeptidases
  • rap1 GTP-Binding Proteins