The short isoform of Tango1 is dispensable for zebrafish survival but is required for skeletal patterning and integrity

Collagen is the most abundant protein in the human body, providing structural stability to connective tissues. It organises and interacts with other proteins to form a complex extracellular matrix (ECM), with loss of collagen in the ECM seen in diseases such as osteoarthritis and osteoporosis. As collagen, and other ECM components, are atypically large proteins, they require specific endoplasmic reticulum (ER) export machinery. A key player in the export of procollagen from the ER is the MIA3 gene product, TANGO1. We introduced mutations to both tango1 isoforms in zebrafish independently to understand the importance of the previously unexplored short isoform in zebrafish development and tissue homeostasis. We show that the long isoform of tango1 (tango1L) is mostly able to compensate for loss of the short isoform (tango1S) in larvae. However, non-collagenous components of the ECM (such as proteoglycans) were disrupted during development, leading to abnormal matrix patterning, visible by electron microscopy. Adult tango1S zebrafish show altered spinal morphology and changes to intervertebral discs, suggesting that tango1S plays a role in skeletal patterning and homeostasis that is independent of the long isoform.