The cell adhesion molecule L1 regulates the expression of choline acetyltransferase and the development of septal cholinergic neurons

Authors

  • Xuezhi Cui,

    1. Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, M4N 3M5, Canada
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  • Ying-Qi Weng,

    1. Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, M4N 3M5, Canada
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  • Isabelle Frappé,

    1. Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, M4N 3M5, Canada
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  • Alison Burgess,

    1. Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, M4N 3M5, Canada
    2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
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  • M. Teresa Girão da Cruz,

    1. Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, M4N 3M5, Canada
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  • Melitta Schachner,

    1. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey
    2. Zentrum fuer Molekulare Neurobiologie, Universitaetskrankenhaus Hamburg-Eppendorf, Hamburg, 20246, Germany
    3. Center for Neuroscience, Shantou University Medical College, Shantou, 515041, P.R. China
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  • Isabelle Aubert

    1. Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, M4N 3M5, Canada
    2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
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  • Xuezhi Cui and Ying-Qi Weng contributed equally to this manuscipt (co-first authorship).

  • Current Affiliations a) Department of Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, M5G 1X38, Canada; b) Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, CNRS 6187, Pôle Biologie-Santé, Poitiers, 86022, France; c) Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, M4N 3M5, Canada; d) Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

  • Funded by NSERCC, CIHR (funding reference number 93603), CNRP, CFI, OIT (IA), ONF Fellowship (IF), OMHF Studentship (AB), and Fundação para a Ciência e a Tecnologia post-doctoral fellowship SFRH/BPD/14581/2003 (MTGdaC).

Isabelle Aubert, Sunnybrook Health Sciences Centre, Research Building, Room S-112, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada. Tel: (416) 480-5831; Fax: (416) 480-5737; E-mail: isabelle.aubert@sri.utoronto.ca

Abstract

Mutations in the L1 gene cause severe brain malformations and mental retardation. We investigated the potential roles of L1 in the regulation of choline acetyltransferase (ChAT) and in the development of septal cholinergic neurons, which are known to project to the hippocampus and play key roles in cognitive functions. Using stereological approaches, we detected significantly fewer ChAT-positive cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca (MS/VDB) of 2-week-old L1-deficient mice compared to wild-type littermates (1644 ± 137 vs. 2051 ± 165, P= 0.038). ChAT protein levels in the septum were 53% lower in 2-week-old L1-deficient mice compared to wild-type littermates. ChAT activity in the septum was significantly reduced in L1-deficient mice compared to wild-type littermates at 1 (34%) and 2 (40%) weeks of age. In vitro, increasing doses of L1-Fc induced ChAT activity in septal neurons with a significant linear trend (*P= 0.0065). At 4 weeks of age in the septum and at all time points investigated in the caudate-putamen (CPu), the number of ChAT-positive neurons and the levels of ChAT activity were not statistically different between L1-deficient mice and wild-type littermates. The total number of cells positive for the neuronal nuclear antigen (NeuN) in the MS/VDB and CPu was not statistically different in L1-deficient mice compared to wild-type littermates, and comparable expression of the cell cycle marker Ki67 was observed. Our results indicate that L1 is required for the timely maturation of septal cholinergic neurons and that L1 promotes the expression and activity of ChAT in septal neurons.

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