NEUREXIN-III-ALPHA - EXTENSIVE ALTERNATIVE SPLICING GENERATES MEMBRANE-BOUND AND SOLUBLE FORMS

The structure of neurexin IIIalpha was elucidated from overlapping cDNA clones. Neurexin IIIalpha is highly homologous to neurexins Ialpha and IIalpha and shares with them a distinctive domain structure that resembles a cell surface receptor. cDNA cloning and PCR experiments revealed alternative splicing at four positions in the mRNA for neurexin IIIalpha. Alternative splicing was previously observed at the same positions in either neurexin Ialpha or neurexin IIalpha or both, suggesting that the three neurexins are subject to extensive alternative splicing. This results in hundreds of different neurexins with variations in small sequences at similar positions in the proteins. The most extensive alternative splicing of neurexin IIIalpha was detected at its C-terminal site, which exhibits a minimum of 12 variants. Some of the alternatively spliced sequences at this position contain in-frame stop codons, suggesting the synthesis of secreted proteins. None of the sequences of the other splice sites in this or the other two neurexins include stop codons. RNA blot analysis demonstrate that neurexin IIIalpha is expressed in a brain-specific pattern. Our results suggest that the neurexins constitute a large family of polymorphic cell surface proteins that includes secreted variants, indicating a possible role as signaling molecules.