Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

• Published in: The Journal of biological chemistry Vol. 288; no. 40; pp. 28869 - 28880
• Main Authors: Combs, Michelle D., Knutsen, Russell H., Broekelmann, Thomas J., Toennies, Holly M., Brett, Thomas J., Miller, Chantel A., Kober, Daniel L., Craft, Clarissa S., Atkinson, Jeffrey J., Shipley, J. Michael, Trask, Barbara C., Mecham, Robert P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-10-2013; American Society for Biochemistry and Molecular Biology
• Subjects: Alleles; Alternative Splicing - genetics; Amino Acid Sequence; Animals; Bone and Bones - pathology; Bone and Bones - physiopathology; Bone Density; Bone Morphogenetic Protein (BMP); Bone Morphogenetic Proteins - metabolism; Cell Movement; Contractile Proteins - chemistry; Contractile Proteins - deficiency; Contractile Proteins - metabolism; Elastin; Exons - genetics; Extracellular Matrix; Extracellular Matrix Proteins - chemistry; Extracellular Matrix Proteins - deficiency; Extracellular Matrix Proteins - metabolism; Gene Targeting; Genetic Pleiotropy; Hematopoiesis; Leukocyte Count; MAGP; Male; Mice; Mice, Knockout; Microfibril; Molecular Bases of Disease; Molecular Sequence Data; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - metabolism; Neutropenia - metabolism; Neutropenia - pathology; Neutrophils - metabolism; Neutrophils - pathology; Organ Size; Protein Binding; RNA Splicing Factors; RNA Stability - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription, Genetic; Transforming Growth Factor beta - metabolism; Transforming Growth Factor β (TGFβ); Bone Morphogenetic Protein (BMP); Extracellular Matrix; Hematopoiesis; Elastin; Microfibril; Transforming Growth Factor β (TGFβ); MAGP
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.497727

The function of MAGP2 was studied by inactivating its gene (Mfap5−/−) in mice.
Results: Mfap5−/− mice have a neutrophil deficiency and other phenotypes that are different from MAGP1- and fibrillin-deficient animals.
Conclusion: MAGP2 has functional roles in hematopoiesis and in vessel wall maintenance.
Significance: Characterization of MAGP2 function is crucial to the identification and treatment of microfibril-related disease.
Microfibril-associated glycoprotein (MAGP) 1 and 2 are evolutionarily related but structurally divergent proteins that are components of microfibrils of the extracellular matrix. Using mice with a targeted inactivation of Mfap5, the gene for MAGP2 protein, we demonstrate that MAGPs have shared as well as unique functions in vivo. Mfap5−/− mice appear grossly normal, are fertile, and have no reduction in life span. Cardiopulmonary development is typical. The animals are normotensive and have vascular compliance comparable with age-matched wild-type mice, which is indicative of normal, functional elastic fibers. Loss of MAGP2 alone does not significantly alter bone mass or architecture, and loss of MAGP2 in tandem with loss of MAGP1 does not exacerbate MAGP1-dependent osteopenia. MAGP2-deficient mice are neutropenic, which contrasts with monocytopenia described in MAGP1-deficient animals. This suggests that MAGP1 and MAGP2 have discrete functions in hematopoiesis. In the cardiovascular system, MAGP1;MAGP2 double knockout mice (Mfap2−/−;Mfap5−/−) show age-dependent aortic dilation. These findings indicate that MAGPs have shared primary functions in maintaining large vessel integrity. In solid phase binding assays, MAGP2 binds active TGFβ1, TGFβ2, and BMP2. Together, these data demonstrate that loss of MAGP2 expression in vivo has pleiotropic effects potentially related to the ability of MAGP2 to regulate growth factors or participate in cell signaling.