Regulation of Collagen Trafficking Pathways in Homeostasis and Disease
Collagens are the structural components of extracellular matrix (ECM), constituting over 30% of dry body weight in vertebrates. Despite their abundance, mechanisms regulating collagen secretion during tissue homeostasis and under disease conditions remain poorly understood. Using zebrafish chondrocytes as an in vivo model, RNA-seq and differential gene expression analysis were performed to identify genes enriched in chondrocytes. Transcription factor creb3L2 and COPII coat components sec23a and sec24d were found in the enriched gene list. Genetic and biochemical assays showed Creb3L2 directly targets sec24d to facilitate collagen secretion. Mutations disrupting Creb3L2-Sec23a-Sec24d collagen secretory axis lead to craniofacial cartilage malformations in zebrafish. Positional cloning of the zebrafish round mutation disrupting cartilage development were investigated and led to identification of novel trafficking pathway components regulating post-Golgi collagen transport. Reiteration in biobanks, Mendelian condition and zebrafish model confirmed that the pathway is highly conserved in vertebrates. Additionally, gene-based PheWAS study was undertaken in BioVU biobank and to identify the phenome associated with reduced expression of GRIK5 that was subsequently confirmed in functional studies in grik5-depleted zebrafish models revealing novel disease mechanisms.