Knockout of the gene encoding the extracellular matrix protein Sned1 results in craniofacial malformations and early neonatal lethality

The extracellular matrix (ECM) is a fundamental component of multicellular organisms that orchestrates developmental processes and controls cell and tissue organization. Mutations in ECM genes or changes in ECM composition, architecture or abundance have been shown to cause or accompany a plethora of diseases including fibrosis, renal, skeletal and vascular diseases and cancers. We previously identified the ECM protein SNED1 in a proteomic screen comparing the ECM of highly and poorly metastatic human mammary tumor xenografts. We further showed that SNED1 promoted breast cancer metastasis and that its level of expression correlated with survival of breast cancer patients. Here we sought to identify the roles of Sned1 during murine development and physiology. Employing a gene-trap strategy or the introduction of a frameshift mutation, we generated two novel Sned1 knockout mouse strains. Using these models, we showed that Sned1 is essential since homozygous ablation of the gene led to early neonatal lethality. Sned1 is widely expressed in embryos, notably in somitic sclerotomes and neural-crest derivatives. Phenotypic analysis of the few surviving knockout mice obtained revealed a role for Sned1 in the development of the skeleton and neural-crest-derived craniofacial structures since Sned1 knockout resulted in growth defects, nasal cavity occlusion, and craniofacial malformations. Altogether our results demonstrate the requisite role for Sned1 during development and neonatal survival.