Cohesin is a multimeric protein made up of three core subunits in somatic cells: RAD21, SMC3, SMC1A and additionally, either STAG1 or STAG2. Cohesin-STAG1 and cohesin-STAG2 have both redundant and unique functions in key processes such as cell division and transcriptional regulation via genome organization. STAG2 is the most frequently mutated cohesin complex member and is one among only 12 genes that are significantly mutated in at least four cancer types, including acute myeloid leukaemia.
Zebrafish represent a well-established model to study haematopoiesis. Using CRISPR-Cas9 we have generated germline zebrafish mutants for three of four stag paralogs, namely stag1a, stag1b and stag2b. We observed disruption of both primitive and definitive embryonic haematopoiesis in our stag1a mutants, with primitive myeloid skewing and a decrease in the number of definitive haematopoietic stem cells. Our stag1b and stag2b mutants showed a reduction in primitive erythropoiesis and in addition exhibited striking defects in tail development, such as mis-localization of certain cell types and the development of ectopic secondary structures. stag2a transcript is maternally inherited and expressed in the ovary, therefore mutants may not have been recovered owing to a critical role for stag2a in germ cell development.
Our results raise the possibility of unique cell type-specific requirements for the different stag paralogs in zebrafish while confirming their importance in haematopoiesis.