The N-cadherin pro-domain processing regulates synaptogenesis

REINÉS A, BERNIER LP, MCADAM R, BELKAID W, SHAN W, KOCH AW, SÉGUÉLA P, COLMAN DR, DHAUNCHAK AS.

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Año: 2012 vol. 32 p. 6323 - 6334

0270-6474

The adhesion molecule N-cadherin participates in neuronal targeting and in the regulation of synaptic strength and stabilization. It is synthesized as a precursor polypeptide (ProN-cadherin), which is non-adhesive. The Pro-domain is thought to be cleaved in the late Golgi by a furin protease, after which adhesively activated N-cadherin is directed to the cell membrane proportion of ProN-cadherin is sorted to the plasma membrane and that the mature/ immature N-cadherin ratio on the surface increases as neuronal differentiation progresses and synapses form. To study the function of ProN-cadherin when expressed on the neuronal surface, we employed a construct in which the endogenous cleavage site of the immature fragment is mutated and a factor Xa cleavage site is generated. Overexpression of ProN-cadherin had a profoundly negative effect on synapse number, measured as a decrease in the number of synaptophysin and PSD-95 puncta and by functional labeling of presynaptic boutons with the FM4-64 dye.  Synapse reduction was overcome after factor Xa was applied to the cultures. Our results demonstrate that non-adhesive ProN-cadherin is expressed in neurons and sorted to the plasma membrane where it acts as a negative regulator of synapse formation. We propose that the dynamic ratio of mature/immature N-cadherin on the neuronal surface is a novel mechanism by which neurons regulate neurite outgrowth and synaptic junction formation.