Identification of Soluble and Membrane-bound Isoforms of the Murine Flt3 Ligand Generated by Alternative Splicing of MRNAs

We have recently described a novel hematopoietic growth factor, referred to as the flt3 ligand, that stimulates the proliferation of sub-populations of hematopoietic cells that are enriched for stem and progenitor cells. This factor is a transmembrane protein that undergoes proteolytic cleavage to generate a soluble form of the protein. We have isolated additional flt3 ligand isoforms by PCR that contain an extra exon and encode what are predicted to be either a soluble form of the ligand or a longer version of the transmembrane protein. We have also isolated cDNAs from murine T cell libraries that encode an isoform of the flt3 ligand that has an unusual C-terminus. This isoform results from a failure to splice out an intron during mRNA processing. The protein encoded by this cDNA is expressed on the cell surface, where it is biologically active. However, this novel isoform does not appear to give rise to a soluble form of the protein. Regulation of mRNA splicing is likely to control the generation of cell bound or soluble forms of this hematopoietic growth factor. Genetic mapping studies localize the gene encoding the flt3 ligand to the proximal portion of mouse chromosome 7 and to human chromosome 19q13.3.