Globin gene expression in developing erythrocytes is under the control of locus control regions (LCRs), which appear to interact directly with a remarkably limited array of trans-acting factors. One of the most important of these is NF-E2, which is an obligate heterodimer of hematopoietic-specific p45 and ubiquitous p18 subunits. NF-E2 is believed to provide the major enhancer function for transcription of the globin genes. By a strategy involving homologous recombination in embryonal stem (ES) cells we have generated mice lacking p45 NF-E2 and found them to manifest anemia and severe thrombocytopenia in the face of otherwise normal development. The anemia is evident only after birth and the mice usually die of hemorrhage; megakaryocytes are present in slightly increased numbers. These findings have important implications for LCR function and platelet development. This proposal describes studies on these aspects of blood cells in mice lacking p45 NF-E2. We seek to establish the nature and causes of anemia in these mice, to identify cellular compensatory mechanisms for the absence of the factor, to develop a system for studying the erythroid effect without the confounding feature of blood loss, to begin a rational approach toward the molecular study of NF-E2 function in the differentiation of megakaryocytes and other hematopoietic cells, and to examine the effects of the absence of p18 NF-E2 in vivo. Molecular, histologic and ultrastructural studies will be combined with mouse breeding experiments and transgenesis to achieve these aims.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL003290-01
Application #
2211486
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (F1))
Project Start
1995-05-01
Project End
1998-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215