Hess, I., Iwanami, N., Schorpp, M., and Boehm, T. (2013) Zebrafish model for allogeneic hematopoietic cell transplantation not requiring preconditioning. Proceedings of the National Academy of Sciences of the United States of America. 110(11):4327-32.
Recent work on vertebrate hematopoiesis has uncovered the presence of deeply rooted similarities between fish and mammals
at molecular and cellular levels. Although small animal models such as zebrafish are ideally suited for genetic and chemical
screens, the study of cellular aspects of hematopoietic development in lower vertebrates is severely hampered by the complex
nature of their histocompatibility-determining genes. Hence, even when hosts are sublethally irradiated before hematopoietic
cell transplantation, stable and long-term reconstitution by allogeneic stem cells often fails. Here, we describe the unexpected
observation that transplantation and maintenance of allogeneic hematopoietic stem cells in zebrafish homozygous for the c-mybt25127 allele, carrying a missense mutation (Ile181Asn) in the DNA binding domain can be achieved without prior conditioning. Using
this model, we examined several critical parameters of zebrafish hematopoiesis in a near-physiological setting. Limiting dilution
analysis suggests that the kidney marrow of adult zebrafish harbors about 10 transplantable hematopoietic stem cells; this
tissue also contains thymus-settling precursors that colonize the thymic rudiment within days after transplantation and initiate
robust T-cell development. We also demonstrate that c-myb mutants can be stably reconstituted with hematopoietic cells carrying specific genetic defects in lymphocyte development,
exemplifying one of the many potential uses of this model in experimental hematology.