Lack of evidence that fibrillin1 regulates bone morphogenetic protein 4 activity in kidney or lung

• Published in: Developmental dynamics Vol. 252; no. 6; pp. 761 - 769
• Main Authors: McKnite, Autumn, Kim, Hyung‐Seok, Silva, Joshua, Christian, Jan L.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-06-2023; Wiley Subscription Services, Inc
• Subjects: Alleles; Animals; BMP4; Bone Morphogenetic Protein 2; Bone morphogenetic protein 4; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein 4 - metabolism; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins - metabolism; Cleavage; Defects; Female; Females; fibrillin1; Hypotheses; kidney; Kidney - metabolism; Kidneys; Lethality; Ligands; lung; Lungs; Mice; mouse; Proteins; BMP4; lung; kidney; mouse; fibrillin1
• ISSN: 1058-8388; 1097-0177
• DOI: 10.1002/dvdy.578

Background
The Bone morphogenetic protein 4 (BMP4) precursor protein is cleaved at two sites to generate an active ligand and inactive prodomain. The ligand and prodomain form a noncovalent complex following the first cleavage, but dissociate after the second cleavage. Transient formation of this complex is essential to generate a stable ligand. Fibrillins (FBNs) bind to the prodomains of BMPs, and can regulate the activity of some ligands. Whether FBNs regulate BMP4 activity is unknown.
Results
Mice heterozygous for a null allele of Bmp4 showed incompletely penetrant kidney defects and females showed increased mortality between postnatal day 6 and 8. Removal of one copy of Fbn1 did not rescue or enhance kidney defects or lethality. The lungs of Fbn1+/− females had enlarged airspaces that were unchanged in Bmp4+/−;Fbn1+/− mice. Additionally, removal of one or both alleles of Fbn1 had no effect on steady state levels of BMP4 ligand or on BMP activity in postnatal lungs.
Conclusions
These findings do not support the hypothesis that FBN1 plays a role in promoting BMP4 ligand stability or signaling, nor do they support the alternative hypothesis that FBN1 sequesters BMP4 in a latent form, as is the case for other BMP family members.
Key Findings
Removal of one copy of Fbn1 does not rescue or exacerbate kidney defects or lethality in Bmp4 null heterozygotes.
Removal of one copy of Bmp4 does not rescue or exacerbate lung defects in Fbn1 null heterozygotes.
BMP4 protein levels and activity are unchanged in the lungs of Fbn1 mutants.
These findings do not support a role for FBN1 in regulating BMP4 activity.