LAR TYROSINE PHOSPHATASE RECEPTOR - PROXIMAL MEMBRANE ALTERNATIVE SPLICING IS COORDINATED WITH REGIONAL EXPRESSION AND INTRANEURONAL LOCALIZATION

Examination of null-mutant Drosophila and Leukocyte Common Antigen-Rel ated (LAR)-deficient transgenic mice has demonstrated that the LAR pro tein tyrosine phosphatase (PTP) receptor promotes neurite outgrowth. I n the absence of known ligands, the mechanisms by which LAR-type PTP r eceptors are regulated are unknown. We hypothesized that an alternativ ely spliced eleven amino acid proximal membrane segment of LAR (LAR al ternatively spliced element-a; LASE-a) contributes to regulation of LA R function. Human, rat and mouse LAR cDNA sequences demonstrated that the predicted eleven amino acid inserts in rat and mouse are identical and share nine of eleven residues with the human insert. LASE-a splic ing led to the introduction of a Ser residue into LAR at a position an alogous to Ser residues undergoing regulated phosphorylation in other PTPs. In-situ studies revealed increasingly region-specific expression of LASE-a containing LAR transcripts during postnatal development. RT -PCR analysis of cortical and hippocampal tissue confirmed that the pr oportion of LAR transcripts containing LASE-a decreases during develop ment. Immunostaining of cultured PC12 cells, cerebellar granule neuron s, dorsal root ganglia and sciatic nerve sections with antibody direct ed against the LASE-a insert demonstrated signal in cell bodies but li ttle if any along neurites. In contrast, staining with antibody direct ed to a separate domain of LAR showed accumulation of LAR along neurit es. The findings that LASE-a splicing is conserved across human, rat a nd mouse, that the LASE-a insert introduces a Ser at a site likely to be targeted for regulated phosphorylation and that developmentally reg ulated splicing is coordinated with specific regional and intraneurona l localization point to important novel potential mechanisms regulatin g LAR-type tyrosine phosphatase receptor function in the nervous syste m. (C) 1998 Elsevier Science B.V. All rights reserved.