IRA O. DAAR, Ph. D.

Laboratory of Leukocyte Biology, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center, National Institutes of Health

Dr. Daar obtained his Ph.D. degree from the State University of New York at Buffalo (Roswell Park Cancer Center Division) where he studied the molecular defects underlying common glycolytic enzyme deficiencies. He then did his postdoctoral training with Dr. George Vande Woude, investigating signal transduction events elicited by certain oncogenes and what cell cycle control points they might influence.

The Xenopus embryo is well suited for investigations of differentiation processes because the frog has a well characterized and invariant cell fate map and cell lineage can be easily traced during experiments. Mutant receptors, ligands and other proteins can be ectopically expressed in embryos. Thus, their effects on signal transduction and differentiation can be assessed morphologically, histologically, as well as biochemically in a developing vertebrate. The laboratory is currently investigating the role of Xek (Xenopus Elk-like Kinase) as well as Xlerk (Xenopus Ligand for Eph Receptor Kinases) in the determination of cell fate using the Xenopus oocyte and embryo systems. Another project recently started in the laboratory examines the regulation and function of Xmeis, a novel family of Xenopus homeodomain proteins whose murine homologues are involved in myeloid leukemogenesis.

We have shown that Xek is expressed during neurulation and transcripts are found at low levels in most tissues. However, abundant expression is observed throughout the entire brain, the trigeminal facial ganglion, branchial arches, and the retina of the swimming tadpole suggesting that Xek may play a role in the development or function of the central nervous system. We have cloned a candidate ligand, Xlerk, that is expressed at low levels in many tissues, but is particularly abundant in the olfactory bulb, olfactory epithelium, hindbrain and eye of the developing frog. In our studies, this transmembrane protein appears to have effects on cell adhesion when it is expressed in the developing embryo as determined by morphological criteria. We will be examining the effects of Xlerk on cell adhesion molecules and various signal transduction events using biochemical techniques. Additionally, mutational analysis of the protein will be performed and functionally assayed in the frog system.

The laboratory is also currently studying a novel homeobox protein, meis 1, that has some homology to the human oncogene product, pbx-1, discovered in human pre-B cell leukemias. While, Xmeis is ubiquitously expressed, our in situ hybridization analysis shows very specific staining in the ventral forebrain, hindbrainspinal chord, and mesenchymal tissues during embryonic development. Since, homeodomain proteins play an integral role in determining embryonic axes, segmental identity and regulating cell differentiation, we feel this is family of proteins is likely to be important during development. Xmeis as well as mutant Xmeis products will be introduced into developing embryos and their effects on developmental processes and their influence on the expression of other developmentally regulated genes will be examined.

We believe that understanding the mechanism by which receptors and transcription factors signal differentiation will improve our understanding of oncogenesis, since most neoplasias appear to result from failure of proliferating cells to respond to differentiation signals.

Recent Publications:

• Matten W et al. Mol Cell Biol 1994;14:4419-4426

• Fukasawa K et al. Oncogene 1995; 11:1447-1457

• Jones T et al. Oncogene 1995;10:1111-1117

• Moskow J, et al. Mol Cell Biol 1995;15:5434-5443

Last revised on September 16, 1996, by D. Derse