Abstract
Background The extracellular matrix (ECM) is a fundamental component of multicellular organisms that orchestrates developmental processes and controls cell and tissue organization. We previously identified the novel ECM protein SNED1 as a promoter of breast cancer metastasis and showed that its level of expression negatively correlated with survival of breast cancer patients. Here we sought to identify the roles of SNED1 during murine development and in physiology.
Results We generated two novel Sned1 knockout mouse strains and showed that Sned1 is essential since homozygous ablation of the gene led to ~67% early neonatal lethality. Phenotypic analysis of the surviving knockout mice obtained revealed a role for SNED1 in the development of craniofacial and skeletal structures since Sned1 knockout resulted in growth defects, nasal cavity occlusion, and craniofacial malformations. Sned1 is widely expressed in embryos, notably in neural-crest derivatives. We further show here that mice with a neural-crest-cell-specific deletion of Sned1 survive, but display facial anomalies partly phenocopying the global knockout mice.
Conclusions Our results demonstrate requisite roles for SNED1 during development and neonatal survival. Importantly, the deletion of 2q37.3 in humans, a region that includes the SNED1 locus, has been associated with facial dysmorphism and short stature.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding information This work was funded in part by the Howard Hughes Medical Institute, of which ROH is an Investigator, a DOD Innovator Award W81XWH-14-1-0240 (ROH), the NIH/NCI Tumor Microenvironment Network U54-CA163109 (ROH), in part by the core grant to the Koch Institute (NIH/NCI P30-CA14051) and by a start-up fund from the Department of Physiology and Biophysics at the University of Illinois at Chicago to AN. AB is the recipient of a Provost Graduate Research Award and an Award for Graduate Research from the UIC Graduate College, KJ is the recipient of a UIC Honors College Research Grant and an award from the LAS Undergraduate Research Initiative at UIC, EDLF is the recipient of a UIC L@S GANAS research fellowship.
In this revised version, we provide evidence for a role of SNED1 in neural crest cells, since mice with a neural-crest-cell-specific deletion of Sned1 survive, but display craniofacial anomalies partly recapitulating the phenotype presented by global Sned1 knockout mice.