Rbx2 regulates neuronal migration through different cullin 5-RING ligase adaptors

Dev Cell. 2013 Nov 25;27(4):399-411. doi: 10.1016/j.devcel.2013.09.022. Epub 2013 Nov 7.

Abstract

Morphogenesis requires the proper migration and positioning of different cell types in the embryo. Much more is known about how cells start and guide their migrations than about how they stop when they reach their destinations. Here we provide evidence that Rbx2, a subunit of the Cullin 5-RING E3 ubiquitin ligase (CRL5) complex, stops neocortical projection neurons at their target layers. Rbx2 mutation causes neocortical and cerebellar ectopias dependent on Dab1, a key signaling protein in the Reelin pathway. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7 is upregulated during projection neuron migration, and unscheduled SOCS7 expression stops migration prematurely. Cerebellar development requires Rbx2 but not SOCS7, pointing to the importance of other CRL5 adaptors. Our results suggest that CRL5 adaptor expression is spatiotemporally regulated to modulate Reelin signaling and ensure normal neuron positioning in the developing brain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Blotting, Western
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cell Movement*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology*
  • Neurons / metabolism
  • Phosphorylation
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Protein Ligases / physiology*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Adhesion Molecules, Neuronal
  • Dab1 protein, mouse
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • SOCS7 protein, mouse
  • Suppressor of Cytokine Signaling Proteins
  • Ubiquitin
  • RNF7 protein, human
  • Ubiquitin-Protein Ligases
  • Serine Endopeptidases
  • reelin protein