Growth Cone Adhesion And Motility

Summary

Principal Investigator: KARL PFENNINGER
Abstract: The axon's growing tip, the nerve growth cone advances by amoeboid locomotion, a process that involves concerted regulation of the actin cytoskeleton and cell adhesion. Growth cone adhesion is not well understood, but recent data indicate that amyloid precursor protein (APP) is enriched in growth cones and associated with their adhesions. This project will test the hypotheses that APP is involved in the regulation of integrin-mediated growth cone adhesion, and that APP affects growth cone motility in vitro and in vivo. The specific aims are to test these hypotheses by: (1) analyzing growth cone spreading and adhesion in conditions of APP and integrin gain and loss of function in vitro;and (2) studying axonal growth and sprouting in vivo, in mutant mice mis-expressing APP. These aims will be pursued with a combination of cell imaging, molecular and biochemical approaches as well as genetically engineered mouse models. The proposed studies are expected to provide new data on the growth cone's adhesion mechanism and, thus, are important for our understanding of axonal growth and pathfinding in development. Furthermore, results are expected to yield insights into the so far little understood function of APP, especially during nervous system development. As APP is over-expressed in Down syndrome, the expected data are likely to provide new insights into possible causes of cognitive deficits in Down syndrome children, and they also will impact our understanding of pathogenic processes in Alzheimer's disease.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Amyloid precursor protein is an autonomous growth cone adhesion molecule engaged in contact guidance
    Lucas J Sosa
    Department of Pediatrics and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA
    PLoS ONE 8:e64521. 2013
  2. pmc Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome
    Lucas J Sosa
    3Department of Pediatrics, University of Colorado, Mailbox 8313, 12800 E 19th Ave, Aurora, CO 80045, USA
    FASEB J 28:195-205. 2014
  3. pmc Group IVA phospholipase A₂ is necessary for growth cone repulsion and collapse
    Staci D Sanford
    Department of Pediatrics, Neuroscience Program, and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA
    J Neurochem 120:974-84. 2012
  4. pmc Functional complexity of the axonal growth cone: a proteomic analysis
    Adriana Estrada-Bernal
    Department of Pediatrics and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, United States of America
    PLoS ONE 7:e31858. 2012

Scientific Experts

  • KARL PFENNINGER
  • Lucas J Sosa
  • Adriana Estrada-Bernal
  • Staci D Sanford
  • R Guo
  • M Hanna
  • Nienke L Postma
  • Jorge Busciglio
  • Jared Bergman
  • Thomas J Glorioso
  • John M Kittelson
  • Bo Goen Yun
  • Christina C Leslie
  • Robert C Murphy
  • Glenn C Simon
  • Kirk C Hansen

Detail Information

Publications4

  1. pmc Amyloid precursor protein is an autonomous growth cone adhesion molecule engaged in contact guidance
    Lucas J Sosa
    Department of Pediatrics and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA
    PLoS ONE 8:e64521. 2013
    ..It follows that APP is an independently operating cell adhesion molecule that affects the GC's phenotype on APP-binding matrices including laminin, and that it is likely to affect axon pathfinding in vivo...
  2. pmc Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome
    Lucas J Sosa
    3Department of Pediatrics, University of Colorado, Mailbox 8313, 12800 E 19th Ave, Aurora, CO 80045, USA
    FASEB J 28:195-205. 2014
    ..The results suggest that APP overexpression may perturb axonal pathfinding and circuit formation in developing DS brain...
  3. pmc Group IVA phospholipase A₂ is necessary for growth cone repulsion and collapse
    Staci D Sanford
    Department of Pediatrics, Neuroscience Program, and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, USA
    J Neurochem 120:974-84. 2012
    ..These studies identify a novel, early step in Sema3A-signaling and a PLA(2) necessary for growth cone repulsion and collapse...
  4. pmc Functional complexity of the axonal growth cone: a proteomic analysis
    Adriana Estrada-Bernal
    Department of Pediatrics and Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, Colorado, United States of America
    PLoS ONE 7:e31858. 2012
    ..Our study provides a resource for further research and amplifies the relatively recently developed concept that the axonal growth cone is equipped with proteins capable of performing a highly diverse range of functions...