Spatially Dependent Dynamic MAPK Modulation by the Nde1-Lis1-Brap Complex Patterns Mammalian CNS

• Published in: Developmental cell 2013-05, Vol.25 (3), p.241-255
• Main Authors: Lanctot, Alison A., Peng, Chian-Yu, Pawlisz, Ashley S., Joksimovic, Milan, Feng, Yuanyi
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1534-5807; 1878-1551
• 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. [Display omitted] •CNS development is guided by graded mitogens and morphogens from the midline•Nde1 and Lis1 regulate CNS development by interpreting midline signals differentially•A Nde1-Lis1-Brap complex modulates spatially dependent MAPK signaling•The dynamic MAPK threshold permits individualized cell fate regulation Signaling centers along the CNS midline produce overlapping mitogenic gradients that guide CNS development. Lanctot et al. show that Nde1-Lis1 double-deficient mice lose specific progenitors/neurons distal to the midline but gain midline epithelial cells. They implicate Nde1-Lis1 and Brap interaction in modulating spatially dependent MAPK signaling for position-dependent cell fate regulation.