Long form of latent TGF-β binding protein 1 (Ltbp1L) is essential for cardiac outflow tract septation and remodeling

Latent TGF-beta binding protein 1 ( LTBP1) is a member of the LTBP/ fibrillin family of extracellular proteins. Due to the usage of different promoters, LTBP1 exists in two major forms, long ( L) and short ( S), each expressed in a temporally and spatially unique fashion. Both LTBP1 molecules covalently interact with latent TGF-beta and regulate its function, presumably via interaction with the extracellular matrix ( ECM). To explore the in vivo role of Ltbp1 in mouse development, at the time when only the L isoform is expressed, we mutated the Ltbp1L locus by gene targeting. Ltbp1L- null animals die shortly after birth from defects in heart development, consisting of the improper septation of the cardiac outflow tract ( OFT) and remodeling of the associated vessels. These cardiac anomalies present as persistent truncus arteriosus ( PTA) and interrupted aortic arch ( IAA), which are associated with the faulty function of cardiac neural crest cells ( CNCCs). The lack of Ltbp1L in the ECM of the septating OFT and associated vessels results in altered gene expression and function of CNCCs and decreased Tgf-beta activity in the OFT. This phenotype reveals a crucial role for Ltbp1L and matrix as extracellular regulators of Tgf-beta activity in heart organogenesis.