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The Journal of Neuroscience, January 7, 2004, 24(1):238-247; doi:10.1523/JNEUROSCI.4519-03.2004

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Development/Plasticity/Repair
Neurite Outgrowth by the Alternatively Spliced Region of Human Tenascin-C Is Mediated by Neuronal 71 Integrin

Mary Lynn T. Mercado, ^* Alam Nur-e-Kamal, ^* Hsing-Yin Liu, ^* Stephane R. Gross, ^* Reza Movahed, and Sally Meiners

Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

The region of tenascin-C containing only alternately spliced fibronectin type-III repeat D (fnD) increases neurite outgrowth by itself and also as part of tenascin-C. We previously localized the active site within fnD to an eight amino acid sequence unique to tenascin-C, VFDNFVLK, and showed that the amino acids FD and FV are required for activity. The purpose of this study was to identify the neuronal receptor that interacts with VFDNFVLK and to investigate the hypothesis that FD and FV are important for receptor binding. Function-blocking antibodies against both 7 and 1 integrin subunits were found to abolish VFDNFVLK-mediated process extension from cerebellar granule neurons. VFDNFVLK but not its mutant, VSPNGSLK, induced clustering of neuronal 1 integrin immunoreactivity. This strongly implicates FD and FV as important structural elements for receptor activation. Moreover, biochemical experiments revealed an association of the 71 integrin with tenascin-C peptides containing the VFDNFVLK sequence but not with peptides with alterations in FD and/or FV. These findings are the first to provide evidence that the 71 integrin mediates a response to tenascin-C and the first to demonstrate a functional role for the 71 integrin receptor in CNS neurons.

View larger version (34K): [in this window] [in a new window]   Figure 1. Structure of human tenascin-C. A, Organization of the tenascin-C molecule. This diagram is adapted from Aukhil et al. (1993). The N termini of three arms are joined to form a trimer, and two trimers are connected via a disulfide bond (S-S) to form a hexamer. Each arm consists of 14 domains with homology to epidermal growth factor (EGF), 8-17 FN-III repeats depending on alternative RNA splicing, and a single fibrinogen (fbg) domain. The universal FN-III repeats (fn1-5 and fn6-8) are present in all tenascin-C splice variants. The largest tenascin-C splice variant contains nine alternatively spliced FN-III repeats (designated A1, A2, A3, A4, B, AD1, AD2, C, and D, or fnA-D), which are missing in the shortest splice variant. B, Crystal structure of universal tenascin-C FN-III domain 3 (fn3). This structure is adapted from Leahy et al. (1992) and consists of six exposed loops and seven strands. The 91 integrin recognition sequence EIDGIELT, which corresponds to the neurite outgrowth-promoting sequence VFDNFVLK in fnD, is highlighted and includes portions of an exposed loop and adjacent strand.

 

Key words: tenascin-C; FN-III repeat; alternatively spliced region; synthetic peptide; site-directed modifications; neurite outgrowth; 71 integrin

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Received Oct 3, 2003; accepted October 16, 2003.

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