Knockout of the gene encoding the extracellular matrix proteinSNED1results in early neonatal lethality and craniofacial malformations

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 breast cancer patient survival. Here, we sought to identify the roles of SNED1 during murine development. Results We generated two novel Sned1 knockout mouse strains and showed that Sned1 is essential since homozygous ablation of the gene led to early neonatal lethality. Phenotypic analysis of the surviving knockout mice 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 by cell populations undergoing epithelial‐to‐mesenchymal transition, such as the neural crest cells. We further show 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.

A pan-cancer analysis of matrisome proteins reveals CTHRC1and LOXL2 as major ECM regulators across cancers

“…SNED1(Sushi, nidogen and EGF like domain containing protein-1) is a glycoprotein known to be involved in embryonic development [22]. Our pan-cancer analysis of matrisome genes differentially expressed and affecting survival in TCGA cancer types, identified SNED1 to be significantly downregulated in bladder, breast, colon, brain, kidney, lung, ovarian, adrenal, prostate, rectal, skin, testicular and uterine cancers while it was upregulated in only thymus cancer ( Figure 2A, C ).…”

“…SNED1 was recently discovered as a ECM glycoprotein whose exact function remains unknown [22,27]. SNED1 knockout mice die perinatally showing significant growth defects [22].…”

“…SNED1 was recently discovered as a ECM glycoprotein whose exact function remains unknown [22,27]. SNED1 knockout mice die perinatally showing significant growth defects [22]. SNED1 is highly expressed by mammary tumors in mice, its knockdown causing fewer lung lesions [4], though the mechanisms by which it regulates cancer progression remains largely unknown [4].…”

Time-lapsed proteomics reveals a role for the novel protein, SNED1, in modulating ECM composition and protein folding

“…Mouse embryonic fibroblasts (MEFs) were previously isolated from embryos of Sned1 LacZ-Neo/LacZ- Neo ( Sned1 KO ) mice [52]. MEFs were first immortalized and then transduced with retroviral constructs to achieve stable expression of either the SNED1_GFP fusion protein (SNED1_GFP) or GFP alone (control), as previously described [40].…”

Crosstalk between basal extracellular matrix adhesion and building of apical architecture during morphogenesis

“…Important effectors of integrins are Talin, which interacts with the actin cytoskeleton, and the pseudokinase integrin-linked kinase (ILK) which interacts with microtubules [MTs, ( Akhtar and Streuli, 2013 ; Klapholz et al, 2015 ; Levi et al, 2006 ; Zervas et al, 2001 )]. Interfering with integrin-mediated cell adhesion leads to morphological defects in many epithelia ( Ambrosini et al, 2019 ; Fernandes et al, 2014 ; Goodwin et al, 2016 ; Ismat et al, 2013 ; Levi et al, 2006 ; Pastor-Pareja and Xu, 2011 ; Schöck and Perrimon, 2003 ) and conditions that affect bECM composition result in severe morphogenetic defects ( Barqué et al, 2020 ; Dor-On et al, 2017 ; Jones et al, 2020 ; Messal et al, 2019 ; Thomas et al, 2018 ).…”