Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage

Autor: Shweta Singh, Wendy E. Kutz, Lauren W. Wang, Dieter P. Reinhardt, Michael W. Jenkins, Timothy J. Mead, Lauren C. Beene, Suneel S. Apte
Rok vydání: 2018
Předmět:
0301 basic medicine
musculoskeletal diseases
Male
congenital
hereditary
and neonatal diseases and abnormalities
Fibrillin-2
Fibrillin-1
macromolecular substances
Eye
Article
Extracellular matrix
03 medical and health sciences
Mice
0302 clinical medicine
ADAMTS Proteins
Fibrillin Microfibrils
In vivo
Genes
Reporter
medicine
Animals
Humans
Ectopia lentis
skin and connective tissue diseases
Muscle
Skeletal
Molecular Biology
Lung
Skin
Mice
Knockout
Metalloproteinase
integumentary system
Chemistry
Brachydactyly
Gene Expression Regulation
Developmental
medicine.disease
Molecular biology
Weill–Marchesani syndrome
Mice
Inbred C57BL
Disease Models
Animal
Weill-Marchesani Syndrome
030104 developmental biology
HEK293 Cells
Lac Operon
030220 oncology & carcinogenesis
Microfibrils
Proteolysis
Blood Vessels
Female
Signal Transduction
Zdroj: Matrix Biol
ISSN: 1569-1802
Popis: Mutations in the secreted metalloproteinase ADAMTS10 cause recessive Weill-Marchesani syndrome (WMS), comprising ectopia lentis, short stature, brachydactyly, thick skin and cardiac valve anomalies. Dominant WMS caused by FBN1 mutations is clinically similar and affects fibrillin-1 microfibrils, which are a major component of the ocular zonule. ADAMTS10 was previously shown to enhance fibrillin-1 assembly in vitro. Here, Adamts10 null mice were analyzed to determine the impact of ADAMTS10 deficiency on fibrillin microfibrils in vivo. An intragenic lacZ reporter identified widespread Adamts10 expression in the eye, musculoskeletal tissues, vasculature, skin and lung. Adamts10(−/−) mice had reduced viability on the C57BL/6 background, and although surviving mice were slightly smaller and had stiff skin, they lacked brachydactyly and cardiovascular defects. Ectopia lentis was not observed in Adamts10(−/−) mice, similar to Fbn1(−/−) mice, most likely because the mouse zonule contains fibrillin-2 in addition to fibrillin-1. Unexpectedly, in contrast to wild-type eyes, Adamts10(−/−) zonule fibers were thicker and immunostained strongly with fibrillin-2 antibodies into adulthood, whereas fibrillin-1 staining was reduced. Furthermore, fibrillin-2 staining of hyaloid vasculature remnants persisted post-natally in Adamts10(−/−) eyes. ADAMTS10 was found to cleave fibrillin-2, providing an explanation for persistence of fibrillin-2 at these sites. Thus, analysis of Adamts10(−/−) mice led to identification of fibrillin-2 as a novel ADAMTS10 substrate and defined a proteolytic mechanism for clearance of ocular fibrillin-2 at the end of the juvenile period.
Databáze: OpenAIRE
Externí odkaz: