Hematopoiesis is a complex developmental process that involves stem cell generation, followed by the commitment of multipotent progenitors and the differentiation of mature blood cells within distinct lineages. Seminal to these intricate events is the coordinated activation or repression of various hematopoietic transcription factors that function combinatorially to direct lineage-specific gene expression. In vertebrates, many of these factors have been identified based on their role as trans-regulators of blood cell expressed genes or their characterization as loci that are chromosomally interrupted or rearranged in specific leukemias. A hematopoietic system also exists in the model organism Drosophila and recent studies have demonstrated that genes essential for blood cell development in the fly represent functional homologues of certain of the hematopoietic factors found in higher eukaryotes. Concerning transcriptional regulators, the utilization of fly genetics has allowed for the rapid functional analysis of the GATA factor Serpent, Friend of GATA factor Ushaped, and Runx-related protein Lozenge in blood cell specification and differentiation. This proposal further analyzes aspects of the expression, interaction, and function of these essential regulators and novel hematopoietic reagents will be used to screen for additional genes required for this complex process. The research objectives will be to characterize the expression and function of a newly discovered blood cell isoform of Serpent, determine the specialized roles of Serpent and U-shaped in the distinct cellular events of embryonic and larval hematopoiesis, and conduct a genome-wide screen for genes that function in crystal cell specification and differentiation. Since recent studies have demonstrated a compelling cross species conservation of genes controlling hematopoiesis, the characterization of these known transcriptional regulators and newly identified genetic players should provide needed insights into fundamental mechanisms controlling blood cell production and their disorders, including leukemia in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071540-04
Application #
6993565
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Thomas, John
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$331,767
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko et al. (2014) bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche. Biochem Biophys Res Commun 453:467-72
Kroeger Jr, Paul T; Shoue, Douglas A; Mezzacappa, Frank M et al. (2013) Knockdown of SCF(Skp2) function causes double-parked accumulation in the nucleus and DNA re-replication in Drosophila plasmatocytes. PLoS One 8:e79019
Tokusumi, Yumiko; Tokusumi, Tsuyoshi; Shoue, Douglas A et al. (2012) Gene regulatory networks controlling hematopoietic progenitor niche cell production and differentiation in the Drosophila lymph gland. PLoS One 7:e41604
Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Hopkins, Dawn W et al. (2011) Germ line differentiation factor Bag of Marbles is a regulator of hematopoietic progenitor maintenance during Drosophila hematopoiesis. Development 138:3879-84
Sorrentino, Richard Paul (2010) Large standard deviations and logarithmic-normality: the truth about hemocyte counts in Drosophila. Fly (Austin) 4:327-32
Lam, Victoria K; Tokusumi, Tsuyoshi; Cerabona, Donna et al. (2010) Specific cell ablation in Drosophila using the toxic viral protein M2(H37A). Fly (Austin) 4:338-43
Tokusumi, Yumiko; Tokusumi, Tsuyoshi; Stoller-Conrad, Jessica et al. (2010) Serpent, suppressor of hairless and U-shaped are crucial regulators of hedgehog niche expression and prohemocyte maintenance during Drosophila larval hematopoiesis. Development 137:3561-8
Tokusumi, Tsuyoshi; Sorrentino, Richard Paul; Russell, Mark et al. (2009) Characterization of a lamellocyte transcriptional enhancer located within the misshapen gene of Drosophila melanogaster. PLoS One 4:e6429
Tokusumi, Tsuyoshi; Shoue, Douglas A; Tokusumi, Yumiko et al. (2009) New hemocyte-specific enhancer-reporter transgenes for the analysis of hematopoiesis in Drosophila. Genesis 47:771-4
Sorrentino, Richard Paul; Tokusumi, Tsuyoshi; Schulz, Robert A (2007) The Friend of GATA protein U-shaped functions as a hematopoietic tumor suppressor in Drosophila. Dev Biol 311:311-23

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