Fundamentals of NCAM Expression, Function, and Regulation of Alternative Splicing in Neuronal Differentiation

The neural cell adhesion molecule (NCAM; CD56) is a member of the immunoglobulin protein superfamily. It has been described as a key molecule for the regulation of neuronal differentiation, synaptogenesis, memory formation, and neuronal plasticity. Alternative splicing gives rise to at least 20–30 NCAM isoforms in mice and humans, NCAM120, NCAM140, and NCAM180 being the more abundant. There are many different modes of alternative splicing; the difference between NCAM140 and NCAM180 is the inclusion or exclusion of an alternative exon. During neuronal differentiation, the alternative splicing pattern of NCAM changes, favoring the expression of NCAM180 to the detriment of NCAM140. In this work we review the most relevant information about NCAM structure and function and present the molecular basis of alternative splicing and its regulation with particular emphasis on how changes in chromatin structure are key for the regulation of NCAM splicing during neuronal differentiation and upon membrane depolarization.