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Knockout of the gene encoding the extracellular matrix protein SNED1 results in early neonatal lethality and craniofacial malformations

View ORCID ProfileAnna Barqué, View ORCID ProfileKyleen Jan, Emanuel De La Fuente, View ORCID ProfileChristina L. Nicholas, View ORCID ProfileRichard O. Hynes, View ORCID ProfileAlexandra Naba
doi: https://doi.org/10.1101/440081
Anna Barqué
1Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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Kyleen Jan
1Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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Emanuel De La Fuente
2Department of Orthodontics, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
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Christina L. Nicholas
2Department of Orthodontics, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
3Department of Anthropology, College of Liberal Arts and Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
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Richard O. Hynes
4Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
5Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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  • For correspondence: anaba@uic.edu rohynes@mit.edu
Alexandra Naba
1Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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  • For correspondence: anaba@uic.edu rohynes@mit.edu
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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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted July 09, 2020.
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Knockout of the gene encoding the extracellular matrix protein SNED1 results in early neonatal lethality and craniofacial malformations
Anna Barqué, Kyleen Jan, Emanuel De La Fuente, Christina L. Nicholas, Richard O. Hynes, Alexandra Naba
bioRxiv 440081; doi: https://doi.org/10.1101/440081
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Knockout of the gene encoding the extracellular matrix protein SNED1 results in early neonatal lethality and craniofacial malformations
Anna Barqué, Kyleen Jan, Emanuel De La Fuente, Christina L. Nicholas, Richard O. Hynes, Alexandra Naba
bioRxiv 440081; doi: https://doi.org/10.1101/440081

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