title: N-cadherin prodomain processing regulates synaptogenesis.
abstract: Classical cadherins, which are adhesion molecules functioning at the CNS synapse, are synthesized as adhesively inactive precursor proteins in the endoplasmic reticulum (ER). Signal sequence and prodomain cleavage in the ER and Golgi apparatus, respectively, activates their adhesive properties. Here, we provide the first evidence for sorting of nonadhesive precursor N-cadherin (ProN) to the neuronal surface, where it coexists with adhesively competent mature N-cadherin (N-cad), generating a spectrum of adhesive strengths. In cultured hippocampal neurons, a high ProN/N-cad ratio downregulates synapse formation. Neurons expressing genetically engineered uncleavable ProN make markedly fewer synapses. The synapse number can be rescued to normality by depleting surface ProN levels through prodomain cleavage by an exogenous protease. Finally, prodomain processing is developmentally regulated in the rat hippocampus. We conclude that it is the ProN/N-cad ratio and not mature N-cad alone that is critical for regulation of adhesion during synaptogenesis.
authors.affiliation: The Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada. areines@ffyb.uba.ar
authors.forename: Analía
authors.initials: A
authors.lastname: Reinés
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Bernier
authors.forename: Robyn
authors.initials: R
authors.lastname: McAdam
authors.forename: Wiam
authors.initials: W
authors.lastname: Belkaid
authors.forename: Weisong
authors.initials: W
authors.lastname: Shan
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Koch
authors.forename: Philippe
authors.initials: P
authors.lastname: Séguéla
authors.forename: David R
authors.initials: DR
authors.lastname: Colman
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Dhaunchak
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D055495:Neurogenesis / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure*
chemical_list: D015820:Cadherins