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Dis Model Mech. 2016 Nov 1;9(11):1367-1374. Epub 2016 Sep 1.

Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice.

Author information

1
Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
2
Department of Molecular Genetics, Cancer Genomics Centre, Erasmus MC, 3015 CN Rotterdam, The Netherlands.
3
Department of Radiation Oncology, Erasmus MC, 3015 CN Rotterdam, The Netherlands.
4
Department of Vascular Surgery, Erasmus MC, 3015 CN Rotterdam, The Netherlands.
5
Department of Molecular Hematology, University of Frankfurt Medical School, 60590 Frankfurt am Main, Germany.
6
Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
7
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
8
Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany anja.sterner-kock@uk-koeln.de.

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/R mice showed a dramatically reduced lifespan compared to Ltbp4S-/- or Fibulin-4R/R mice, which survive to adulthood. This dramatic reduction in survival of Ltbp4S-/-;Fibulin-4R/R mice 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/R mice suffer from aortic aneurysm formation combined with aortic tortuosity, in contrast to Ltbp4S-/- or Fibulin-4R/R mice. 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.

KEYWORDS:

Aortic tortuosity; Defective alveolar septation; Elastic fibers; Fibulin-4; Latent-transforming growth factor beta-binding protein 4 (Ltbp-4)

PMID:
27585882
PMCID:
PMC5117228
DOI:
10.1242/dmm.026005
[Indexed for MEDLINE]
Free PMC Article

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