2009), and potentiation of BDNF binding

and signaling upon removal of polysialic acid (Burgess and Aubert 2006). L1 was first described as the NGF-inducible large external glycoprotein (NILE) (Bock et al. 1985; Prince et al. 1991). L1′s expression is clearly induced by NGF (Salton et al. 1983) but the mechanisms linking L1, NGF, and ChAT expression remain to be established. Blocking TrkA or p75NTR is known to abolish Inhibitors,research,lifescience,medical NGF-induced ChAT (Nonner et al. 2000). In contrast, NGF-induced L1 expression can occur in absence of p75NTR (Walsh et al. 1998) or independently of the high-affinity NGF receptor (Itoh et al. 1995). Our in vitro data clearly show that L1-Fc induces ChAT activity and future studies will investigate potential mechanisms. It is possible that L1′s activation of ChAT is carried out in part through FGFR (Maness Inhibitors,research,lifescience,medical and Schachner 2007), which is known to be a strong ChAT activator

(find more Grothe et al. 1989), which is similar to what we have found with C3d, an NCAM mimetic peptide (Burgess et al. 2009). In conclusion, L1 regulates the expression of ChAT, it influences levels of ChAT activity, and it is required for the proper development of septal cholinergic neurons in the first 2 postnatal weeks. It remains to be established whether improving cholinergic neurotransmission Inhibitors,research,lifescience,medical can rescue cognitive deficits in mice lacking L1. The promoting effects of L1 on ChAT activity and on the development of cholinergic neurons are of significance in the design of therapeutic strategies aiming to alleviate mental retardation and disorders of cholinergic deficits, as in Alzheimer’s disease. Acknowledgments This work was funded by Natural Science and Engineering Inhibitors,research,lifescience,medical Research Council of Canada (NSERCC), Canadian Institutes of Health Research (CIHR Funding Reference Number 93603), Canadian Neurotrauma Research Program (CNRP), Canada Foundation for Innovation (CFI), Ontario Innovation

Inhibitors,research,lifescience,medical Trust (OIT) (IA), Ontario Neurotrauma Foundation (ONF) Fellowship (IF), Ontario Mental Health Foundation (OMHF) Studentship (AB), and Fundação para a Ciência e a Tecnologia post-doctoral fellowship SFRH/BPD/14581/2003 (MTGdaC). M. Schachner is a New Jersey Professor of Spinal Cord Research. The authors found would also like to thank A. Tandon for his critical reading of the article; S. Bell for editing and proof-reading the article; MBF Bioscience and Geoff Greene for stereology support; A. Ypsilanti and S. Rideout for assistance in experiments; and G. Loers, I. Jakovcevski, and P. Putthoff for a generous supply of L1-Fc, reagents, and mice. We are grateful to W. B. Stallcup for the L1 antibody. We appreciated the expert assistance of G. Knowles at the Centre for Cytometry and Scanning Microscopy, and E. Yang at the Proteomics Core Facility of the Toronto Angiogenesis Research Centre, both located at the Sunnybrook Research Institute and supported by a CIHR Multi-User Equipment & Maintenance Grant.