title: Protein interacting with NIMA (never in mitosis A)-1 regulates axonal growth cone adhesion and spreading through myristoylated alanine-rich C kinase substrate isomerization.
abstract: Axonal growth cone motility requires precise regulation of adhesion to navigate the complex environment of the nervous system and reach its target. Myristoylated alanine-rich C kinase substrate (MARCKS) protein is enriched in the developing brain and plays an important, phosphorylation-dependent role in the modulation of axonal growth cone adhesion. The ratio of phospho-MARCKS (MARCKS-P) to total MARCKS controls adhesion modulation and spreading of the axonal growth cone. Pin1, a peptidyl-prolyl cis/trans isomerase (PPIase) that recognizes and binds to phosphorylated serine/threonine residues preceded by a proline (pSer/Thr-Pro) is also expressed in the developing brain. Here, we show that Pin1 is present in the growth cone, interacts with MARCKS-P, and regulates its dephosphorylation. We also described morphological alterations in the corpus callosum and cerebral cortex fibers of the Pin1 knockout mouse brain that may be caused by the misregulation of MARCKS-P and alterations of neuronal adhesion. We have shown that MARCKS, a critical protein in the movement of neuronal growth cones, is in turn regulated by both phosphorylation and cis-trans peptidyl isomerization mediated by Pin1. In the absence of Pin1, MARCKS is hyperphosphorylated, leading to loss of adhesions, and collapse of the growth cone. The Pin1 KO mice exhibited disturbed neuronal projections from the cerebral cortex and reduced white matter tracks such as the corpus callosum. This study highlights a novel function of Pin1 in neurodevelopment.
authors.affiliation: Department of Pediatrics and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Lucas J
authors.initials: LJ
authors.lastname: Sosa
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Departamento de Química Biológica-CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba-CONICET, Córdoba, Argentina.
authors.forename: Florentyna
authors.initials: F
authors.lastname: Bustos Plonka
authors.affiliation: Departamento de Química Biológica-CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba-CONICET, Córdoba, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Oksdath
authors.affiliation: Departamento de Química Biológica-CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba-CONICET, Córdoba, Argentina.
authors.forename: Alvaro F
authors.initials: AF
authors.lastname: Nieto Guil
authors.affiliation: Departamento de Química Biológica-CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba-CONICET, Córdoba, Argentina.
authors.forename: Santiago
authors.initials: S
authors.lastname: Quiroga
authors.affiliation: Department of Pediatrics and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Pfenninger
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D005260:Female; D020439:Growth Cones / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D007536:Isomerism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000502:physiology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C000606850:Pin1 protein, mouse
keywords: MARCKS; Pin1; brain development; corpus callosum; growth cone adhesion; isomerization