LTBP‑4L and LTBP‑4S are two isoforms of the extracellular matrix protein latent transforming growth factor β-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, 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 life span compared to Ltbp4S‑/− and 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‑/− and 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.
- Received April 20, 2016.
- Accepted August 15, 2016.
- © 2016. Published by The Company of Biologists Ltd
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