Barry H. Paw
Department of Medicine
Brigham and Women's Hospital
Karp Research Building, Room 06.213
One Blackfan Circle
Boston, MA 02115-5713
Tel: (617) 355-9008
Fax: (617) 355-9064
Web Page: The Paw Lab Page
6 postdoctoral fellows, 1 medical resident, 1 technician
Genetics of Blood Cell Development
The focus of our 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, our lab has undertaken genetic (mutagenesis) screens to isolate zebrafish mutants with defects in red cells and thrombocytes (platelet-equivalent). 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 zebrafish embryos and complementary model systems, such as mouse (cultured cells and transgenic mice) and yeast.
Mitochondrial Iron Metabolism
Recently, our 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. Our group is now investigating the biochemical properties of the Mitoferrin transporter in red cell development in zebrafish, mouse, yeast, and cell culture models. Our 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.
- Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Gwynn B, Lambert AJ, Traver D, Trede NS, Barut BA, Minet E, Zhou Y, Donovan A, Brownlie A, Balzan R, Weiss MJ, Peters LL, Kaplan J, Zon LI, Paw BH. Mitoferrin is essential for erythroid iron assimilation. Nature (2006) 440:96-100.
- Nilsson R, Schultz IJ, Pierce EL, Soltis KA, Naranuntarat A, Ward DM, Baughman J, Paradkar PN, Kingsley PD, Culotta VC, Kaplan J, Palis J, Paw BH*, Mootha VK*. Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metabolism (2009) 10:119-30. *[co-corresponding senior authors]
- Chen W, Paradkar PN, Li L, Pierce EL, Langer NB, Takahashi-Makise N, Hyde BB, Shirihai OS, Ward DM, Kaplan J, Paw BH. Abcb10 physically interacts with mitoferrin1 (slc25a37) to enhance its stability and function in the erythroid mitochondria. Proc. Natl. Acad. Sci. USA (2009) 106:16263-68.
- Schultz IJ, Chen C, Paw BH*, Hamza I*. Iron and porphyrin trafficking in heme biogenesis. J. Biol. Chem. (2010) 285:26753-9. [*co-corresponding senior authors].
- Amigo JD, Yu M, Troadec M-B, Gwynn B, Cooney JD, Lambert AJ, Chi NC, Weiss MJ, Peters LL, Kaplan J, Cantor AB, Paw BH. Identification of distal cis-regulatory elements at the mouse mitoferrin loci using zebrafish transgenesis. Mol. Cell. Biol. (2011), in press. [E-pub ahead of print, 01/19/11; doi:10.1128/MCB.01010-10].
BBS webpage updated 2/3/2011