title: Spatially dependent dynamic MAPK modulation by the Nde1-Lis1-Brap complex patterns mammalian CNS.
abstract: 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.
authors.affiliation: Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Lanctot
authors.forename: Chian-Yu
authors.initials: CY
authors.lastname: Peng
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Pawlisz
authors.forename: Milan
authors.initials: M
authors.lastname: Joksimovic
authors.forename: Yuanyi
authors.initials: Y
authors.lastname: Feng
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D004843:Epistasis, Genetic; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D019579:Neocortex / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D025941:Protein Interaction Mapping; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; C531336:Nde1 protein, mouse; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse