title: Abrogation of both short and long forms of latent transforming growth factor-β binding protein-1 causes defective cardiovascular development and is perinatally lethal.
abstract: Latent transforming growth factor-β binding protein-1 (LTBP-1) is an extracellular protein that is structurally similar to fibrillin and has an important role in controlling transforming growth factor-β (TGF-β) signaling by storing the cytokine in the extracellular matrix and by being involved in the conversion of the latent growth factor to its active form. LTBP-1 is found as both short (LTBP-1S) and long (LTBP-1L) forms, which are derived through the use of separate promoters. There is controversy regarding the importance of LTBP-1L, as Ltbp1L knockout mice showed multiple cardiovascular defects but the complete null mice did not. Here, we describe a third line of Ltbp1 knockout mice generated utilizing a conditional knockout strategy that ablated expression of both L and S forms of LTBP-1. These mice show severe developmental cardiovascular abnormalities and die perinatally; thus these animals display a phenotype similar to previously reported Ltbp1L knockout mice. We reinvestigated the other "complete" knockout line and found that these mice express a splice variant of LTBP-1L and, therefore, are not complete Ltbp1 knockouts. Our results clarify the phenotypes of Ltbp1 null mice and re-emphasize the importance of LTBP-1 in vivo.
authors: Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors: Masahito
authors: M
authors: Horiguchi
authors: Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Medicine, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors: Vesna
authors: V
authors: Todorovic
authors: Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors: Krassimira
authors: K
authors: Hadjiolova
authors: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany.
authors: Ralf
authors: R
authors: Weiskirchen
authors: Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Medicine, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address: Daniel.Rifkin@nyumc.org.
authors: Daniel B
authors: DB
authors: Rifkin
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005804:Genes, Lethal; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology / Q000662:veterinary*; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta
keywords: Conditional knockout mice; Latent TGF-β binding protein; Persistent truncus arteriosus; Transforming growth factor β