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Genetics of Blood Cell Development

The focus of Barry Paw’s laboratory research is studying genes important for red cell and platelet development using the zebrafish as a genetic model organism. The genetic program for development of the hematopoietic system is conserved from zebrafish to higher organisms. Using the advantages of zebrafish genetics and developmental biology, the Paw lab has undertaken forward genetic (mutagenesis) screens to isolate zebrafish mutants with defects in red cells. The genes disrupted in these mutants are then identified by a combination of positional and candidate cloning strategies as a way to gain insight into the genetic basis of vertebrate hematopoiesis. The biological functions of the identified genes are studied in in zebrafish embryos and complementary model systems, such as mouse (cultured cells and transgenic mice) and yeast.

Mitochondrial Iron Metabolism

Recently, his group has identified the gene disrupted in the frascati mutation as a novel mitochondrial metal transporter, Mitoferrin (Mfrn, Slc25A37), crucial for red cell development. Loss of function of the Mitoferrin transporter results in severe anemia and an erythroid maturation arrest due to defects in mitochondrial iron assimilation. The function of this gene is highly conserved through evolution from yeasts to zebrafish and mammals. His group is now investigating the biochemical properties of the Mitoferrin transporter in red cell development in zebrafish, mouse, yeast, and cell culture models. His group has identified the association between patients with anemia and hepatic failure with a nonfunctional, mispliced Mitoferrin mRNA.  This example proves the utility of genetic screens in zebrafish as a means for gene discovery and uncovering the genetic basis of diseases.

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