Universität zu Köln

Bultmann-Mellin, Insa, Essers, Jeroen, van Heijingen, Paula M., von Melchner, Harald, Sengle, Gerhard and Sterner-Kock, Anja ORCID: 0000-0002-2877-7116 (2016). Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice. Dis. Model. Mech., 9 (11). S. 1367 - 1375. CAMBRIDGE: COMPANY OF BIOLOGISTS LTD. ISSN 1754-8411

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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 type1C(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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bultmann-Mellin, Insa UNSPECIFIED UNSPECIFIED UNSPECIFIED Essers, Jeroen UNSPECIFIED UNSPECIFIED UNSPECIFIED van Heijingen, Paula M. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Melchner, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Sterner-Kock, Anja UNSPECIFIED orcid.org/0000-0002-2877-7116 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-257089
DOI:	10.1242/dmm.026005
Journal or Publication Title:	Dis. Model. Mech.
Volume:	9
Number:	11
Page Range:	S. 1367 - 1375
Date:	2016
Publisher:	COMPANY OF BIOLOGISTS LTD
Place of Publication:	CAMBRIDGE
ISSN:	1754-8411
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ABDOMINAL AORTIC-ANEURYSM; RECESSIVE CUTIS LAXA; GROWTH-FACTOR-BETA; BINDING-PROTEIN 4; LUNG DEVELOPMENT; ARTERIAL TORTUOSITY; MARFAN-SYNDROME; IN-VIVO; MUTATIONS; GENE Multiple languages Cell Biology; Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25708