John R. Nambu

Research Interests

Gene Regulation and Programmed Cell Death in Drosophila Development

Three fundamental aspects of metazoan development are pattern formation, cell differentiation, and cell death. The first two processes ensure that cells are correctly specified and acquire appropriate functional properties. The third permits the controlled elimination of cells that have failed in the first two, or that may have transient or deleterious functions. Our laboratory utilizes Drosophila as a model system to study these processes.

One focus is on the mechanisms through which Fish-hook, a Sox HMG-domain protein, regulates gene expression during diverse developmental events. Using genetics and cell biology we have shown that Fish-hook is essential for segmentation, nervous system organization, appendage formation, and oogenesis. Molecular and biochemical studies have defined Fish-hook DNA binding, DNA bending, and transcriptional activation properties. Fish-hook directly regulates expression of downstream target genes, including even-skipped and slit, through chromatin architectural functions as well as direct transcriptional activation. We are currently analyzing interactions between Fish-hook and several other gene regulatory proteins.

A second research focus is on the mechanisms which govern a cellís decision to survive or die during development. In particular, we have analyzed functional interactions between several key regulators of programmed cell death, including the Reaper, Hid, and Grim death activators, and the DIAP1 and DIAP2 death inhibitors. We have identified synergistic and dose-dependent interactions between these proteins. Use of a genetic modifier screen has revealed potential cell death regulatory roles for several genes in the Ubiquitin/Proteasome protein turnover pathway. We are currently determining whether these genes may influence the activation of cell death processes by regulating the relative levels of death activators and inhibitors.

Representative Publications

Schreader, B.A. and Nambu, J.R. 2004. A fine balance for life and death decisions. Nature Structural and Molecular Biology, 11: 386-388.

Schreader, B.A., Wang,Y., and Nambu, J.R. 2003. Drosophila morgue and the intersection between programmed cell death and ubiquitination. Apoptosis, 8: 129-139.

Wing, J.P., Schreader, B.A., Yokokura, T., Wang, Y., Andrews, P.S., Huseinovic, N., Dong, C.K., Schwartz, L.M., White, K., Nambu, J.R. 2002. Drosophila Morgue is a novel F box/ubiquitin conjugase domain protein important in grim-reaper mediated programmed cell death. Nature Cell Biol., 4: 451-456.

Wing, J.P., Karres, J.S., Ogdahl, J.L., Zhou, L., Schwartz, L.M., Nambu, J.R.. 2002. Drosophila sickle is a novel grim-reaper cell death activator. Curr. Biol., 12: 131-135.

Wing, J.P., Schwartz, L.M., and Nambu, J.R. 2001. The RHG motifs of Drosophila Reaper and Grim are important for their distinct cell death-inducing abilities. Mech. Devel., 102: 193-203.

Ma, Y., Certel, K., Gao, Y., Niemitz, E., Mosher, J., Mukherjee, A., Mutsuddi, M., Huseinovic, N., Crews, S.T., Johnson, W.A., and Nambu, J. R. 2000. Functional interactions between Drosophila bHLH/PAS, Sox, and POU transcription factors regulate CNS midline expression of the slit gene. Journal of Neuroscience, 20: 4596-4605.

Mukherjee, A., Shan, X., Mutsuddi, M., Ma, Y., and Nambu, J. R. 2000. The Drosophila Sox gene, fish-hook, is required for postembryonic development. Developmental Biology, 217: 91-106.

Hu Y., Cascone, P. J., Cheng, L., Sun, D., Nambu, J. R. , Schwartz, L. M. 1999. Lepidopteran DALP, and its mammalian ortholog HIC-5, function as negative regulators of muscle differentiation. Proceedings of the National Academy of Sciences USA, 96: 10218-10223.

Mutsuddi, M. and Nambu, J. R. 1998. Neural disease: Drosophila degenerates for a good cause. Current Biology, 8: R809-811.

Wing, J. P., Zhou, L., Schwartz, L. M., and Nambu, J. R. 1998. Distinct cell killing properties of the Drosophila reaper, head involution defective, and grim genes. Cell Death and Differentiation, 5: 930-939.

Wing, J. P. and Nambu, J. R. 1998. Apoptosis in Drosophila. in Apoptosis Regulatory Genes. C.S. Potten, C. Booth, and J. W. Wilson, eds. Chapman and Hall, London, pp. 205-241.

Zhou, L., Schnitzler, A,. Agapite, J., Schwartz. L.M., Steller, H. and Nambu J.R. 1997. Cooperative functions of the reaper and head involution defective genes in the programmed cell death of Drosophila central nervous system midline cells. Proceedings National Academy of Sciences, USA 94: 5131-5136.

Zhou, L., Xiao, H., and Nambu, J.R. 1997. CNS Midline to Mesoderm Signaling in Drosophila. Mechanisms of Development, 67: 59-68.

Nambu, P. and Nambu, J. R. 1996. The Drosophila fish-hook gene encodes a HMG domain protein essential for segmentation and CNS development. Development, 122: 3467-3475.

Xiao, H., Hrdlicka, L., and Nambu, J. R. 1996. Alternate functions of the single-minded and rhomboid genes in development of the Drosophila ventral neuroectoderm. Mechanisms of Development, 58: 65-74.

Zhou, L. Zhou, L., Hashimi, H., Schwartz, L.M. and Nambu, J.R. 1995. Programmed Cell Death in the Drosophila Central Nervous System Midline. Current Biology, 5: 784-790.