Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor Beta 1a (TGFß1a)

Proprotein convertase subtilisin/kexin (PCSK) enzymes convert proproteins into bioactive end-products. While other PCSK enzymes are known to be essential for biological processes ranging from cholesterol metabolism to host-defense, the in vivo importance of the evolutionary ancient PCSK7 has remained enigmatic. Here, we quantified the expressions of all PCSKs during the first week of fish development and in several tissues. PCSK7 expression was ubiquitous and evident already during the early development. To compare mammalian and zebrafish PCSK7 we prepared homology models, which demonstrated remarkable structural conservation. When the PCSK7 function in developing larvae was inhibited we found that PCSK7 deficient fish have defects in various organs, including the brain, eye and otic vesicle, and this results in mortality within 7 days post fertilization. A genome-wide analysis of PCSK7 dependent gene expression showed that, in addition to developmental processes, also several immune related pathways are regulated by PCSK7. Specifically, the mRNA expression of the cytokine TGFß1a is compromised in PCSK7 deficient larvae and TGFß1a morphant fish displayed phenotypical similarities with PCSK7 morphants, which underscores the importance of this cytokine in the zebrafish development. Targeting PCSK activity has emerged as a strategy for treating human diseases. Our results suggest that inhibiting PCSK7 might interfere with normal vertebrate development.