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Human Molecular Genetics Advance Access published online on September 13, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm264
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Lack of Fibulin-3 Causes Early Aging and Herniation, but not Macular Degeneration in Mice

Precious J. McLaughlin1, Benjamin Bakall1, Jiwon Choi2, Zhonglin Liu3, Takako Sasaki4, Elaine C. Davis2, Alan D. Marmorstein1,5 and Lihua Y. Marmorstein1,6,*

1 Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ 2 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada 3 Department of Radiology, University of Arizona, Tucson, AZ 4 Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 5 Optical Sciences Center, University of Arizona, Tucson, AZ 6 Department of Physiology, University of Arizona, Tucson, AZ

* To whom correspondence should be addressed at: Department of Ophthalmology and Vision Science, University of Arizona, 655 N Alvernon Way, Suite 108, Tucson, AZ 85711, U.S.A. Tel: 1 5206260447. Fax: 1 5206260457; Email: Lmarmorstein{at}eyes.arizona.edu

Received August 14, 2007; Revised September 11, 2007; Accepted September 11, 2007

A mutation in the EFEMP1 gene causes Malattia Leventinese (ML), an inherited macular degenerative disease with strong similarities to age-related macular degeneration (AMD). EFEMP1 encodes fibulin-3, an extracellular matrix (ECM) protein of unknown function. To investigate its biological role, the murine Efemp1 gene was inactivated through targeted disruption. Efemp1-/- mice exhibited reduced reproductivity, and displayed an early onset of aging-associated phenotypes including reduced life span, decreased body mass, lordokyphosis, reduced hair growth, and generalized fat, muscle, and organ atrophy. However, these mice appeared to have normal wound healing ability. Efemp1-/- mice on a C57BL/6 genetic background developed multiple large hernias including inguinal hernias, pelvic prolapse, and protrusions of the xiphoid process. In contrast, Efemp1-/- mice on a BALB/c background rarely had any forms of hernias, indicating the presence of modifiers for fibulin-3's function in different mouse strains. Histological analysis revealed a marked reduction of elastic fibers in fascia, a thin layer of connective tissue maintaining and protecting structures throughout the body. No apparent macular degeneration associated defects were found in Efemp1-/- mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in fibulin-3 causes macular degeneration. These data demonstrate that fibulin-3 plays an important role in maintaining the integrity of fascia connective tissues and regulates aging.


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