Genomes and Genes
Growth Cone Adhesion And Motility
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
- Amyloid precursor protein is an autonomous growth cone adhesion molecule engaged in contact guidanceLucas 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...
- Dosage of amyloid precursor protein affects axonal contact guidance in Down syndromeLucas 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...
- Group IVA phospholipase A₂ is necessary for growth cone repulsion and collapseStaci 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...
- Functional complexity of the axonal growth cone: a proteomic analysisAdriana 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...