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First published online 13 February 2008
doi: 10.1242/dev.007401
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Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
* Author for correspondence (e-mail: flanagan{at}hms.harvard.edu)
Accepted 9 January 2008
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, CTF
, 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.
Key words: Amyloid precursor protein, Axon, Contactin, L1CAM, Retina
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