Adamts18 deletion results in distinct developmental defects and provides a model for congenital disorders of lens, lung, and female reproductive tract development

Abstract

The ADAMTS family comprises 19 secreted metalloproteinases that cleave extracellular matrix components and have diverse functions in numerous disease and physiological contexts. A number of them remain ‘orphan’ proteases and among them is ADAMTS18, which has been implicated in developmental eye disorders, platelet function and various malignancies. To assess in vivo function of ADAMTS18, we generated a mouse strain with inactivated Adamts18 alleles. In the C57Bl6/Ola background, Adamts18-deficient mice are born in a normal Mendelian ratio, and are viable but show a transient growth delay. Histological examination revealed a 100% penetrant eye defect resulting from leakage of lens material through the lens capsule occurring at embryonic day (E)13.5, when the lens grows rapidly. Adamts18-deficient lungs showed altered bronchiolar branching. Fifty percent of mutant females are infertile because of vaginal obstruction due to either a dorsoventral vaginal septum or imperforate vagina. The incidence of ovarian rete is increased in the mutant mouse strain. Thus, Adamts18 is essential in the development of distinct tissues and the new mouse strain is likely to be useful for investigating ADAMTS18 function in human disease, particularly in the contexts of infertility and carcinogenesis.

The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

“…Mammary gland development in Adamts18 −/− mice. To assess the functional importance of Adamts18 in mammary gland development, we generated mice homozygous for an allele lacking exons 8 and 9, which encode the Zn-binding catalytic site 31 and analyzed their inguinal mammary glands at critical developmental stages by whole mount stereomicroscopy. In prepubertal, 14-dayold WT and Adamts18 −/− littermates, the ductal system was rudimentary and of similar size in both genotypes ( Fig.…”

“…Similarly, targeting downstream Wnt signaling has potential side effects because this signaling pathway is physiologically important for stem cells in many tissues. Based on the mouse model, ADAMTS18 is important for development of specific organs but it does not appear to have an essential function in adult mice 31 . Furthermore, in its extracellular location ADAMTS18 makes it an excellent target for antibody-mediated therapy.…”

SP1‐mediated lncRNA PVT1 modulates the proliferation and apoptosis of lens epithelial cells in diabetic cataract via miR‐214‐3p/MMP2 axis

“…The modulators matrix metalloproteinases (MMPs) family plays critical roles in the TGFβ2-mediated matrix contraction. [26][27][28] Besides, MMP2 is closely correlated with the proliferation of lens epithelial cells. Therefore, lncRNA PVT1 could regulate the HLE B-3 cell biological activity via modulating the MMP2.…”

A Disintegrin and Metalloproteinase with Thrombospondin Motifs 18 Deficiency Leads to Visceral Adiposity and Associated Metabolic Syndrome in Mice

“…In C57Bl6/Ola mice, Adamts18 deletion results in distinct developmental defects, including congenital disorders of the lens, lung, and female reproductive tract development. 29 In humans, ADAMTS18 mutations have been linked to tumorigenesis, 30 eye diseases, 31e33 reduced bone mineral density formation, 34 and white matter integrity of the brain. 35 We have previously reported that ADAMTS18 is associated with platelet lyses and cerebral infarction in a postischemic stroke model.…”