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Abrogation of both short and long forms of latent transforming growth factor-β binding protein-1 causes defective
Masahito Horiguchi1, Vesna Todorovic2, Krassimira Hadjiolova1
1Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Insights
Latent transforming growth factor-β binding protein-1 (LTBP-1) is crucial for cardiovascular development. New knockout mice confirm LTBP-1
Area of Science:
- Extracellular matrix biology
- Molecular and cell biology
- Developmental biology
Background:
- Latent transforming growth factor-β binding protein-1 (LTBP-1) regulates transforming growth factor-β (TGF-β) signaling.
- LTBP-1 exists in short (LTBP-1S) and long (LTBP-1L) forms, with prior conflicting data on LTBP-1L's in vivo importance.
- Previous knockout mouse studies yielded ambiguous results regarding LTBP-1's essential role.
Purpose of the Study:
- To generate and characterize a novel LTBP-1 conditional knockout mouse model.
- To resolve the controversy surrounding the necessity of LTBP-1L.
- To definitively establish the in vivo function of LTBP-1 in cardiovascular development.
Main Methods:
- Generation of a conditional Ltbp1 knockout mouse line using CRISPR/Cas9 technology.
- Phenotypic analysis of knockout mice, including cardiovascular assessments and survival rates.
- Re-examination of previously generated "complete" Ltbp1 knockout mice to identify expression discrepancies.
Main Results:
- Conditional knockout mice lacking both LTBP-1S and LTBP-1L exhibit severe cardiovascular abnormalities and perinatal lethality.
- These findings mirror the phenotype of previously reported LTBP-1L knockout mice.
- Previous "complete" knockout mice were found to express an LTBP-1L splice variant, explaining the lack of a null phenotype.
Conclusions:
- LTBP-1 is essential for normal cardiovascular development in vivo.
- The conditional knockout model provides a clear understanding of LTBP-1's critical role.
- This study resolves previous discrepancies and confirms the importance of LTBP-1 for organismal survival.
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.
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