Evolution of insulin-like growth factor II: characterization of the mouse IGF-II gene and identification of two...

We have cloned the mouse insulin-like growth factor II (IGF-II) gene as a series of overlapping cosmid and lambda recombinants and have characterized its six exons. The gene extends over approximately 12 kb of mouse chromosome 7 and is located 18 kb 3' to the insulin 2 gene and in the same transcriptional polarity. Exons 1-3 encode distinct 5' untranslated regions and are transcribed by three different promoters, P1, P2, and P3, into three IGF-II mRNAs sharing common coding and 3' untranslated sequences. Promoters P2 and P3 each contain a TATA box and appear to direct transcription from single initiation sites. By contrast, exon 1 has three major transcriptional start sites distributed over 556 nucleotides, and P1 lacks a TATA region and other typical transcriptional control sequences. Exons 4-6 code for the 180-amino-acid IGF-II precursor, and exon 6 also contains a 3,045-nucleotide 3' untranslated region which ends at a single polyadenylation site. In addition to six functional IGF-II exons, we identified two 5' "pseudo-exons," which appear to be evolutionarily retained remnants of an alternative promoter-exon cassette that is active in human IGF-II. Loss of the homolog of this promoter, which directs "adult-specific" expression of the IGF-II gene in some human tissues, may explain the disappearance of this growth factor from most murine tissues in the early postnatal period.