MIR retroposon exonization promotes evolutionary variability and generates species-specific expression of IGF-1 splice variants

Giosuè Annibalini, Pamela Bielli, Mauro De Santi, Deborah Agostini, Michele Guescini, Davide Sisti, Serena Contarelli, Giorgio Brandi, Anna Villarini, Vilberto Stocchi, Claudio Sette, Elena Barbieri

Research output: Contribution to journalArticlepeer-review


Insulin-like growth factor (IGF) -1 is a pleiotropic hormone exerting mitogenic and anti-apoptotic effects. Inclusion or exclusion of exon 5 into the IGF-1 mRNA gives rise to three transcripts, IGF-1Ea, IGF-1Eb and IGF-1Ec, which yield three different C-terminal extensions called Ea, Eb and Ec peptides. The biological significance of the IGF-1 splice variants and how the E-peptides affect the actions of mature IGF-1 are largely unknown. In this study we investigated the origin and conservation of the IGF-1 E-peptides and we compared the pattern of expression of the IGF-1 isoforms in vivo, in nine mammalian species, and in vitro using human and mouse IGF-1 minigenes. Our analysis showed that only IGF-1Ea is conserved among all vertebrates, whereas IGF-1Eb and IGF-1Ec are an evolutionary novelty originated from the exonization of a mammalian interspersed repetitive-b (MIR-b) element. Both IGF-1Eb and IGF-1Ec mRNAs were constitutively expressed in all mammalian species analyzed but their expression ratio varies greatly among species. Using IGF-1 minigenes we demonstrated that divergence in cis-acting regulatory elements between human and mouse conferred species-specific features to the exon 5 region. Finally, the protein-coding sequences of exon 5 showed low rate of synonymous mutations and contain disorder-promoting amino acids, suggesting a regulatory role for these domains. In conclusion, exonization of a MIR-b element in the IGF-1 gene determined gain of exon 5 during mammalian evolution. Alternative splicing of this novel exon added new regulatory elements at the mRNA and protein level potentially able to regulate the mature IGF-1 across tissues and species.

Original languageEnglish
Pages (from-to)757-768
Number of pages12
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Issue number5
Publication statusPublished - May 1 2016


  • Alternative splicing
  • IGF-1 isoforms
  • Intrinsically disordered regions
  • Retroposon exonization
  • Synonymous sites

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Genetics
  • Molecular Biology
  • Structural Biology


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