Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system.
The amyloid precursor protein (APP) plays a central role in Alzheimer's disease, but its actions in normal development are not well understood. Here, a tagged APP ectodomain was used to identify extracellular binding partners in developing chick brain. Prominent binding sites were seen in the olfactory bulb and on retinal axons growing into the optic tectum. Co-precipitation from these tissues and tandem mass spectrometry led to the identification of two associated proteins: contactin 4 and NgCAM. In vitro binding studies revealed direct interactions among multiple members of the APP and contactin protein families. Levels of the APP processing fragment, CTFalpha, were modulated by both contactin 4 and NgCAM. In the developing retinotectal system, APP, contactin 4 and NgCAM are expressed in the retina and tectum in suitable locations to interact. Functional assays revealed regulatory effects of both APP and contactin 4 on NgCAM-dependent growth of cultured retinal axons, demonstrating specific functional interactions among these proteins. These studies identify novel binding and functional interactions among proteins of the APP, contactin and L1CAM families, with general implications for mechanisms of APP action in neural development and disease.
Osterfield
Miriam
M
Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Egelund
Rikke
R
Young
Lauren M
LM
Flanagan
John G
JG
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D019062:Cell Adhesion Molecules, Neuron-Glia / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002642:Chick Embryo; D058966:Contactins; D004247:DNA / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000196:embryology* / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism; D013477:Superior Colliculi / Q000196:embryology* / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D019062:Cell Adhesion Molecules, Neuron-Glia; D015816:Cell Adhesion Molecules, Neuronal; D058966:Contactins; D039842:Neural Cell Adhesion Molecule L1; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D004247:DNA