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Mouse embryonic ciliopathies

ADAMTS9 and ADAMTS20 are highly homologous sister proteases with identical domain structure. They play redundant roles during mouse embryonic development. Dual knockdown mouse mutants therefore manifest severe developmental defects resembling human ciliopathies and do not survive past the 15th day of gestation (Movies 1 and 2, Nandadasa et al., Nature Communications 2019). Adamts9+20 mutants manifest severe craniofacial defects including cleft lip and pallet (CL/P), exencephaly (neural tube defects), mandibular hypoplasia, eye defects, umbilical cord defects, left-right body axis elongation defects, soft tissue syndactyly, heart malformations (VSD), tracheoesophageal septation defects and yolk sac vasculature defects. These developmental defects are also known to be caused by disrupted ciliogenesis in other cilia mutant mouse models. A hallmark of the Adamts9+20 mutants is disrupted hedgehog signaling caused by the loss of primary cilia and ECM accumulation due to loss of ECM homeostasis. We will characterize each phenotype and investigate the cellular and molecular mechanisms and the specificity of action (cell autonomous vs non-cell autonomous) using tissue specific knock down strategies in mice and mammalian cell culture models.