Latent TGF-β binding protein-1 deficiency decreases female fertility

Abstract The four latent transforming growth factor-β (TGF-β) binding proteins LTBP1-4 are extracellular matrix-associated proteins playing a critical role in the activation of TGF-β. The LTBP1 gene forms two major transcript variants (i.e. Ltbp1S and Ltbp1L ) that are derived from different promoters. We have previously shown the importance of LTBP1 in vivo by using three different Ltbp1 null mice that were either deleted for exons 1 and 2 ( Ltbp1L knockout), exon 5 ( Ltbp1 Δ Ex5 ), or exon 8 ( Ltbp1 Δ Ex8 ). While the Ltbp1L knockout and the Ltbp1ΔEx8 are perinatal lethal and die of cardiovascular abnormalities, the Ltbp1 Δ Ex5 is viable because it expresses a short form of Ltbp1L that lacks 55 amino acids (Δ55 variant of Ltbp1 ) formed by splicing out exon 5, while lacking the Ltbp1S variant. Since only the Ltbp1 Δ Ex5 mouse is viable, we have used this model to address aspects of puberty, fertility, age-dependent reproduction, and ovary function. We report for the first time a function of LTBP1 in female reproduction. The Ltbp1 Δ Ex5 females showed impaired fertility associated with delayed sexual maturity (p = 0.0074) and ovarian cyst formation in females older than 40 weeks (p = 0.0204).