Thesis

The role of SON in blood development: an analysis of vertebrate hematopoietic proliferation and differentiation

Zebrafish (Danio rerio) is an excellent model organism for studying embryonic vertebrate development due to their conserved genome with humans, external development, and ease of observation under the microscope. The gene SON is found on the twenty-first chromosome of humans and is often overexpressed in patients with leukemias, particularly acute megakaryoblastic leukemia. Previously, we showed that mutations in the mRNA splicing co-factor gene SON cause malformations in human and zebrafish spines and brains. We performed these studies by knocking down the expression of the zebrafish homolog of SON in zebrafish at the single-cell developmental stage with specific morpholinos (MOs). In addition to the brain and spinal malformations we also observed abnormal blood cell levels with son knockdown. We then investigated how blood production was altered when levels of son were lowered. Decreased levels of SON resulted in impaired blood flow and lower amounts of red blood cells when visualized with hbaa:GFP transgenic fish. There was also a reduction in thrombocytes seen with cd41:GFP fish and verified with flow cytometry, and myeloid cells, as seen with mpx:GFP fish. We also saw a significant decrease in the quantity of T cells, visualized with lck:GFP fish. However, when we plated the hematopoietic stem and progenitor cells (HSPCs) from zebrafish with reduced levels of son, we saw no difference in colony forming capability. Further investigation of son and its effect on blood development should establish how misexpression of this gene negatively impacts human health.

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