title: Generation of Fbn1 conditional null mice implicates the extracellular microfibrils in osteoprogenitor recruitment.
abstract: Loss-of-function experiments in mice have yielded invaluable mechanistic insights into the pathogenesis of Marfan syndrome (MFS) and implicitly, into the multiple roles fibrillin-1 microfibrils play in the developing and adult organism. Unfortunately, neonatal death from aortic complications of mice lacking fibrillin-1 (Fbn1(-/-) mice) has limited the scope of these studies. Here, we report the creation of a conditional mutant allele (Fbn1(fneo) ) that contains loxP sites bordering exon1 of Fbn1 and an frt-flanked neo expression cassette downstream of it. Fbn1(fneo/+) mice were crossed with FLPeR mice and the resulting Fbn1(Lox/+) progeny were crossed with Fbn1(+/-) ;CMV-Cre mice to generate Fbn1(CMV-/-) mice, which were found to phenocopy the vascular abnormalities of Fbn1(-/-) mice. Furthermore, mating Fbn1(Lox/+) mice with Prx1-Cre or Osx-Cre mice revealed an unappreciated role of fibrillin-1 microfibrils in restricting osteoprogenitor cell recruitment. Fbn1(Lox/+) mice are, therefore, an informative genetic resource to further dissect MFS pathogenesis and the role of extracellular fibrillin-1 assemblies in organ development and homeostasis.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Cook
authors.forename: Silvia
authors.initials: S
authors.lastname: Smaldone
authors.forename: Carmine
authors.initials: C
authors.lastname: Cozzolino
authors.forename: Maria
authors.initials: M
authors.lastname: del Solar
authors.forename: Sui
authors.initials: S
authors.lastname: Lee-Arteaga
authors.forename: Harikiran
authors.initials: H
authors.lastname: Nistala
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D002454:Cell Differentiation; D000071838:Fibrillin-1; D000071837:Fibrillins; D055785:Gene Knockdown Techniques; D023061:Gene Order; D018390:Gene Targeting / Q000379:methods; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D020894:Microfibrils / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D010641:Phenotype; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines