Spatially dependent dynamic MAPK modulation by the Nde1-Lis1-Brap complex patterns mammalian CNS

Dev Cell. 2013 May 13;25(3):241-55. doi: 10.1016/j.devcel.2013.04.006.


Regulating cell proliferation and differentiation in CNS development requires both extraordinary complexity and precision. Neural progenitors receive graded overlapping signals from midline signaling centers, yet each makes a unique cell fate decision in a spatiotemporally restricted pattern. The Nde1-Lis1 complex regulates individualized cell fate decisions based on the geographical location with respect to the midline. While cells distant from the midline fail to self-renew in the Nde1-Lis1 double-mutant CNS, cells embedded in the signaling centers showed marked overproliferation. A direct interaction between Lis1 and Brap, a mitogen-activated protein kinase (MAPK) signaling threshold modulator, mediates this differential response to mitogenic signal gradients. Nde1-Lis1 deficiency resulted in a spatially dependent alteration of MAPK scaffold Ksr and hyperactivation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions. These results suggest that a molecular complex composed of Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially dependent fashion.

Publication types

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

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Epistasis, Genetic
  • Immunohistochemistry
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Multiprotein Complexes / metabolism
  • Mutation
  • Neocortex / enzymology
  • Neocortex / metabolism*
  • Neocortex / pathology
  • Neurogenesis
  • Neurons / enzymology
  • Neurons / metabolism
  • Neurons / pathology
  • Protein Interaction Mapping
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Structure, Tertiary
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Cell Cycle Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Nde1 protein, mouse
  • Protein Kinases
  • KSR-1 protein kinase
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah1b1 protein, mouse