Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

ABSTRACT Fibulin-2 is an extracellular matrix protein belonging to the five-member fibulin family, of which two members have been shown to play essential roles in elastic fiber formation during development. Fibulin-2 interacts with two major constituents of elastic fibers, tropoelastin and fibrillin-1, in vitro and localizes to elastic fibers in many tissues in vivo. The protein is prominently expressed during morphogenesis of the heart and aortic arch vessels and at early stages of cartilage development. To examine its role in vivo, we generated mice that do not express the fibulin-2 gene (Fbln2) through homologous recombination of embryonic stem cells. Unexpectedly, the fibulin-2-null mice were viable and fertile and did not display gross and anatomical abnormalities. Histological and ultrastructural analyses revealed that elastic fibers assembled normally in the absence of fibulin-2. No compensatory up-regulation of mRNAs for other fibulin members was detected in the aorta and skin tissue. However, in the fibulin-2 null aortae, fibulin-1 immunostaining was increased in the inner elastic lamina, where fibulin-2 preferentially localizes. The results demonstrate that fibulin-2 is not required for mouse development and elastic fiber formation and suggest possible functional redundancy between fibulin-1 and fibulin-2.

[1]  Takako Sasaki,et al.  Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice. , 2007, Human molecular genetics.

[2]  R. Timpl,et al.  A Comparative Analysis of the Fibulin Protein Family , 2007, Journal of Biological Chemistry.

[3]  Takako Sasaki,et al.  Fibrillin-1 Interactions with Fibulins Depend on the First Hybrid Domain and Provide an Adaptor Function to Tropoelastin* , 2007, Journal of Biological Chemistry.

[4]  Tiansen Li,et al.  Molecular Analysis of Fibulin-5 Function during De Novo Synthesis of Elastic Fibers , 2007, Molecular and Cellular Biology.

[5]  G. Hammond,et al.  Evidence That Fibulin Family Members Contribute to the Steroid-dependent Extravascular Sequestration of Sex Hormone-binding Globulin* , 2006, Journal of Biological Chemistry.

[6]  R. Mecham,et al.  Targeted Disruption of Fibulin-4 Abolishes Elastogenesis and Causes Perinatal Lethality in Mice , 2006, Molecular and Cellular Biology.

[7]  A. Shuttleworth,et al.  Fibulin-5 interacts with fibrillin-1 molecules and microfibrils. , 2005, The Biochemical journal.

[8]  T. Tsuda,et al.  Fibulins in development and heritable disease. , 2004, Birth defects research. Part C, Embryo today : reviews.

[9]  L. Greene,et al.  Fibulins: physiological and disease perspectives , 2003, EMBO reports.

[10]  R. Timpl,et al.  Fibulins: a versatile family of extracellular matrix proteins , 2003, Nature Reviews Molecular Cell Biology.

[11]  Masashi Yanagisawa,et al.  Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo , 2002, Nature.

[12]  Tasuku Honjo,et al.  Fibulin-5/DANCE is essential for elastogenesis in vivo , 2002, Nature.

[13]  R. Timpl,et al.  Perinatal Lethality and Endothelial Cell Abnormalities in Several Vessel Compartments of Fibulin-1-Deficient Mice , 2001, Molecular and Cellular Biology.

[14]  R. Timpl,et al.  Fibulin‐2 expression marks transformed mesenchymal cells in developing cardiac valves, aortic arch vessels, and coronary vessels , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[15]  D Heinegård,et al.  The Proteoglycans Aggrecan and Versican Form Networks with Fibulin-2 through Their Lectin Domain Binding* , 2001, The Journal of Biological Chemistry.

[16]  R. Timpl,et al.  Tropoelastin binding to fibulins, nidogen‐2 and other extracellular matrix proteins , 1999, FEBS letters.

[17]  S. Grässel,et al.  Mouse fibulin-2 gene. Complete exon-intron organization and promoter characterization. , 1999, European Journal of Biochemistry.

[18]  T. Sasaki,et al.  Developmental changes in the basement membrane of the normal and hypothyroid postnatal rat testis: segmental localization of fibulin-2 and fibronectin. , 1998, Biology of reproduction.

[19]  R. Timpl,et al.  Dimer model for the microfibrillar protein fibulin‐2 and identification of the connecting disulfide bridge , 1997, The EMBO journal.

[20]  T. Sasaki,et al.  Expression of fibulin-2 by fibroblasts and deposition with fibronectin into a fibrillar matrix. , 1996, Journal of cell science.

[21]  T. Sasaki,et al.  Fibrillin-1 and Fibulin-2 Interact and Are Colocalized in Some Tissues* , 1996, The Journal of Biological Chemistry.

[22]  R. Timpl,et al.  Fibulin‐1 and fibulin‐2 expression during organogenesis in the developing mouse embryo , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[23]  T. Sasaki,et al.  Binding of mouse and human fibulin-2 to extracellular matrix ligands. , 1995, Journal of molecular biology.

[24]  R. Mecham,et al.  Identification of an Elastin Cross-linking Domain That Joins Three Peptide Chains , 1995, The Journal of Biological Chemistry.

[25]  D. Keene,et al.  The association of human fibulin-1 with elastic fibers: an immunohistological, ultrastructural, and RNA study. , 1995, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[26]  R. Timpl,et al.  Fibulin-2 (FBLN2): human cDNA sequence, mRNA expression, and mapping of the gene on human and mouse chromosomes. , 1994, Genomics.

[27]  R. Timpl,et al.  Recombinant expression and structural and binding properties of α1(VI) and α2(VI) chains of human collagen type VI , 1994 .

[28]  T. Sasaki,et al.  Structure and expression of fibulin-2, a novel extracellular matrix protein with multiple EGF-like repeats and consensus motifs for calcium binding , 1993, The Journal of cell biology.

[29]  D. Birk,et al.  Extracellular compartments in tendon morphogenesis: collagen fibril, bundle, and macroaggregate formation , 1986, The Journal of cell biology.

[30]  T. Sasaki,et al.  Extracellular matrix protein fibulin-2 is expressed in the embryonic endocardial cushion tissue and is a prominent component of valves in adult heart. , 1995, Developmental biology.

[31]  R. Timpl,et al.  Recombinant expression and structural and binding properties of alpha 1(VI) and alpha 2(VI) chains of human collagen type VI. , 1994, European journal of biochemistry.

[32]  C. Stewart,et al.  Simple screening procedure to detect gene targeting events in embryonic stem cells. , 1993, Methods in enzymology.