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Normal Isotype Switching in B Cells Lacking the Iµ Exon Splice Donor Site: Evidence for Multiple Iµ-Like Germline Transcripts

Igor I. Kuzin^1,*, Gregory D. Ugine^1,*, Dongming Wu^*, Fay Young^*, Jianzhu Chen and Andrea Bottaro^2,*

^* Departments of Medicine and Microbiology and Immunology, and Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 021139

Ig class switch recombination (CSR) in activated B cells is preceded by the generation of "switch" transcripts from the heavy chain constant region (CH) genes targeted for rearrangement. Switch transcripts include a sterile "I" exon spliced onto the first CH exon. Targeted mutations disrupting the expression or splicing of I exons severely hamper CSR to all tested CH loci, except µ. However, all µ switch transcript mutations tested so far have left the Iµ exon splice donor site intact. To test the possibility that the residual CSR activity in Iµ mutants could be due to splicing of a truncated Iµ exon, we generated new mutants specifically lacking the Iµ splice donor site. Surprisingly, normal CSR was observed in the Iµ splice donor mutants even in the absence of detectable spliced Iµ transcripts. In a search for potential alternative sources of switch-like transcripts in the µ locus, we identified two novel exons which map just upstream of the Sµ region and splice onto the Cµ1 exon. Their expression is detectable from early B cell developmental stages, and, at least in hybridomas, it does not require the Eµ enhancer. These studies highlight a unique structure for the µ locus I exon region, with multiple nested switch transcript-like exons mapping upstream of Sµ. We propose that all of these transcripts directly contribute to µ class switching activity.

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