title: Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice.
abstract: LTBP-4L and LTBP-4S are two isoforms of the extracellular matrix protein latent-transforming growth factor beta-binding protein 4 (LTBP-4). The mutational inactivation of both isoforms causes autosomal recessive cutis laxa type 1C (ARCL1C) in humans and an ARCL1C-like phenotype in Ltbp4-/-mice, both characterized by high postnatal mortality and severely affected elastogenesis. However, genetic data in mice suggest isoform-specific functions for Ltbp-4 because Ltbp4S-/-mice, solely expressing Ltbp-4L, survive to adulthood. This clearly suggests a requirement of Ltbp-4L for postnatal survival. A major difference between Ltbp4S-/-and Ltbp4-/-mice is the matrix incorporation of fibulin-4 (a key factor for elastogenesis; encoded by the Efemp2 gene), which is normal in Ltbp4S-/-mice, whereas it is defective in Ltbp4-/-mice, suggesting that the presence of Ltbp-4L might be required for this process. To investigate the existence of a functional interaction between Ltbp-4L and fibulin-4, we studied the consequences of fibulin-4 deficiency in mice only expressing Ltbp-4L. Resulting Ltbp4S-/-;Fibulin-4R/Rmice showed a dramatically reduced lifespan compared to Ltbp4S-/-or Fibulin-4R/Rmice, which survive to adulthood. This dramatic reduction in survival of Ltbp4S-/-;Fibulin-4R/Rmice correlates with severely impaired elastogenesis resulting in defective alveolar septation and distal airspace enlargement in lung, and increased aortic wall thickness with severely fragmented elastic lamellae. Additionally, Ltbp4S-/-;Fibulin-4R/Rmice suffer from aortic aneurysm formation combined with aortic tortuosity, in contrast to Ltbp4S-/-or Fibulin-4R/Rmice. Together, in accordance with our previous biochemical findings of a physical interaction between Ltbp-4L and fibulin-4, these novel in vivo data clearly establish a functional link between Ltbp-4L and fibulin-4 as a crucial molecular requirement for survival and elastogenesis in mice.
authors: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors: Insa
authors: I
authors: Bultmann-Mellin
authors: Department of Molecular Genetics, Cancer Genomics Centre, Erasmus MC, 3015 CN Rotterdam, The Netherlands.|Department of Radiation Oncology, Erasmus MC, 3015 CN Rotterdam, The Netherlands.|Department of Vascular Surgery, Erasmus MC, 3015 CN Rotterdam, The Netherlands.
authors: Jeroen
authors: J
authors: Essers
authors: Department of Molecular Genetics, Cancer Genomics Centre, Erasmus MC, 3015 CN Rotterdam, The Netherlands.
authors: Paula M
authors: PM
authors: van Heijingen
authors: Department of Molecular Hematology, University of Frankfurt Medical School, 60590 Frankfurt am Main, Germany.
authors: Harald
authors: H
authors: von Melchner
authors: Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
authors: Gerhard
authors: G
authors: Sengle
authors: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany anja.sterner-kock@uk-koeln.de.
authors: Anja
authors: 0000-0002-2877-7116
authors: A
authors: Sterner-Kock
mesh_terms: D000818:Animals; D004549:Elastin / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D053779:Latent TGF-beta Binding Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D016019:Survival Analysis
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D053779:Latent TGF-beta Binding Proteins; D004549:Elastin
keywords: Aortic tortuosity; Defective alveolar septation; Elastic fibers; Fibulin-4; Latent-transforming growth factor beta-binding protein 4 (Ltbp-4)