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BARQUEFALGUERA-DISSERTATION-2022.pdf (71.26 MB)

The Extracellular Matrix Protein SNED1 Regulates Neural Crest Cell Phenotype and Craniofacial Development

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posted on 2022-05-01, 00:00 authored by Anna Barque Falguera
The extracellular matrix (ECM) is a fundamental component of multicellular organisms. It is a complex meshwork of proteins that provides structural and biochemical support to cells. We previously identified the novel ECM protein SNED1 as a promoter of breast cancer metastasis (Naba et al., eLife, 2014) and have recently reported that SNED1 is essential for development since the homozygous ablation of the Sned1 gene resulted in early neonatal lethality (Barqué et al., Dev Dyn, 2020). Interestingly, the few surviving knockout (KO) mice exhibited craniofacial abnormalities, were smaller in size, and had shorter long bones. Since cranial neural crest cells (NCCs) form most of the craniofacial skeleton, for my PhD project I hypothesized that SNED1 influences the behavior of this cell population. To test my hypothesis, I generated an NCC-specific Sned1 KO mouse model. Importantly, Sned1NCC-/NCC- mice survive but present craniofacial anomalies partly phenocopying the global Sned1 KO mice (Barqué et al., Dev Dyn, 2020). To form craniofacial structures, cephalic NCCs first need to delaminate from the neural tube, then migrate towards the frontonasal region, and there differentiate into bone and cartilage, among other cell types. Given the importance of the ECM in guiding cell migration and the fact that SNED1 promotes the dissemination of mammary tumors, I have performed in-situ NCC tracking experiments and in-vitro adhesion and spreading experiments that are pointing for a role of SNED1 in guiding the migration pattern of NCCs during craniofacial morphogenesis. Last, I have focused on identifying the SNED1 receptors (Vallet, Davis, Barqué et al., Biochem J, 2021) and at deciphering the molecular mechanisms activated downstream of SNED1 and leading to cell migration. Of clinical relevance, deletion of 2q37.3, a region that comprises the SNED1 locus, and point mutations in the SNED1 gene have been linked to facial dysmorphism in patients. We thus propose that SNED1 contributes to the phenotype of these patients and that understanding its physiological role in the formation of the craniofacial structures may shed light on some of the features of this syndrome. Last, since metastatic cells share common features with NCC, they both undergo epithelial-to-mesenchymal transition to acquire a migratory phenotype, our studies will allow us to better understand the role of SNED1 in metastasis.

History

Advisor

Naba, Alexandra

Chair

Heydemann, Ahlke

Department

Physiology and Biophysics

Degree Grantor

University of Illinois at Chicago

Degree Level

  • Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Kazlauskas, Andrius Kitajewski, Jan K Cooper, Lyndon F Saxena, Ankur

Submitted date

May 2022

Thesis type

application/pdf

Language

  • en

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