Igf1 Alternative Splicing

Endocrinology

INSULIN-LIKE GROWTH FACTOR-1 3' UNTRANSLATED REGION: STRAINSPECIFIC POLYMORPHISMS AND MOTIFS REGULATING IGF-1 IN OSTEOBLASTS.

--Manuscript Draft-Manuscript Number: Full Title: INSULIN-LIKE GROWTH FACTOR-1 3' UNTRANSLATED REGION: STRAINSPECIFIC POLYMORPHISMS AND MOTIFS REGULATING IGF-1 IN OSTEOBLASTS. IGF1 3' UTR REGULATION Original Article Growth Factors - Cytokines Anne M Delany, Ph.D. University of Connecticut Health Center Farmington, CT UNITED STATES

Short Title: Article Type: Section/Category: Corresponding Author:

Corresponding Author Secondary Information: Corresponding Author's Institution: Corresponding Author's Secondary Institution: First Author: First Author Secondary Information: Order of Authors: Spenser Smith, BS Catherine B. Kessler, BS Vikram Shenoy, BS Clifford J. Rosen, MD Anne M Delany, Ph.D. Order of Authors Secondary Information: Abstract: Reduced IGF-1 levels are associated with low bone mass in humans and mice. C3H/He/J (C3H) mice have higher skeletal IGF-1 and greater bone mass than C57BL/6J (B6). We hypothesized that strain-related genotypic differences in Igf1 affected skeletal function. The Igf1 coding region is nonpolymorphic, but its 3'untranslated region (UTR) is polymorphic between C3H and B6. Using LuciferaseIgf1 3'UTR reporter constructs, we demonstrated that these polymorphic regions did not affect UTR function. IGF-1 splice variants give rise to a common mature IGF-1 peptide, but different E peptides. We identified two splice products, exon 4+6 (Ea) and exon 4+5+6 (Eb, mechano-growth factor), and found their abundance was unchanged during osteoblastic differentiation. The Igf1 3'UTR encoded by exon 6 contains 2 alternative polyadenylation sites. Proximal site use produces a short 3'UTR of ~195 bases, whereas distal site usage results in a ~6300 base UTR. Although the absolute level of Igf1 mRNA did not change during osteoblastic differentiation, distal polyadenylation site usage was significantly increased,...