Ectodomain shedding of nectin-1 regulates the maintenance of dendritic spine density


Address correspondence and reprint requests to Howard J. Federoff, Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA. E-mail:


J. Neurochem. (2012) 120, 741–751.


Synaptic remodeling has been postulated as a mechanism underlying synaptic plasticity and cell adhesion molecules are thought to contribute to this process. We examined the role of nectin-1 ectodomain shedding on synaptogenesis in cultured rat hippocampal neurons. Nectins are Ca2+-independent immunoglobulin-like adhesion molecules, involved in cell-cell adherens junctions. Herein, we show that the processing of nectin-1 occurs by multiple endoproteolytic steps both in vivo and in vitro. We identified regions containing two distinct cleavage sites within the ectodomain of nectin-1. By alanine scanning mutagenesis, two point mutations that disrupt nectin-1 ectodomain cleavage events were identified. Expression of these mutants significantly alters the density of dendritic spines. These findings suggest that ectodomain shedding of nectin-1 regulates dendritic spine density and related synaptic functions.