Alternative splicing variants of proinsulin mRNA and the effects of excess proinsulin on cardiac morphogenesis

• Proinsulin alternative transcripts are expressed in chick and mouse developing heart.
• The translationally inactive proinsulin mRNA predominates during chick morphogenesis.
• Overexpression of proinsulin induces cardiac malformations in chick embryos.
• Tight regulation of extrapancreatic proinsulin is required for normal cardiogenesis.

Alternative forms of proinsulin mRNA with differential translational capacities and unknown significance are expressed in several developing tissues and in the adult pancreas. In the chick embryo developing heart, we observed low expression of the translationally active transcript of embryonic proinsulin (Pro1B), and predominant expression of the intron 1-unspliced variant, translationally inactive. In the embryonic mouse heart, intron 1-unspliced isoform appeared after E12.5. This tight regulation is required for normal development, since overexpression of Pro1B resulted in abnormal cardiac morphogenesis in 40% of chick embryos, and was accompanied by changes in gene expression of Amhc1and Vmhc1.