The central nervous system (CNS) is comprised of a complex yet stereotypic array of diverse cell types. These cells arise from ectodermal precursors, take on unique identities, and come to adopt the specialized functions of neurons and glia. These developmental processes are essential for the proper organization and function of the nervous system and therefore ultimately for numerous aspects of animal physiology and behavior.

The goal of our research is to elucidate the molecular and cellular mechanisms that underlie the development of specific types of nerve cells. To facilitate these studies we have focused our attention on the midline cells within the embryonic central nervous system of Drosophila. There are approximately 25-30 midline neurons and glia per segment, and most of them are uniquely identifiable on the basis of morphological, anatomical, and molecular criteria. They have important developmental functions in mediating the migration of axon projections from lateral nerve cells and also in influencing the differentiation of adjacent ventral epidermal cells.


John R. Nambu

Molecular Genetics of
Nervous System Development
in Drosophila

A significant aspect of midline development is the issue of how undifferentiated midline precursor cells give rise to distinct midline cell types. That is, what are the positional cues, cell-cell interactions, and gene regulation hierarchies that guide the differentiation of individual midline neurons and glia? We are addressing these questions by characterizing the roles of known and novel genes involved in these processes.

This includes the midline transcription factor single-minded, as well as a battery of genes identified by P-element enhancer detector strains, which yield expression of the marker gene beta-galactosidase in some or all of the midline cells during different stages of embryogenesis. These P-element strains will facilitate molecular and genetic studies of genes vital to midline development and function.

The midline cells provide an important model system for studying nerve cell development and promise to yield insight into the generation of specific CNS cell types. Interestingly, distinctive midline cells are also present in the nervous systems of other animals. These cells, which include the roof plate and floor plate of the developing vertebrate spinal cord, appear to have many of the same functional properties as the Drosophila CNS midline cells, suggesting evolutionarily conserved functions of specialized midline cells during the formation of bilaterally symmetric nervous system structures.

Representative Publications:

Nambu, J. R., Franks, R. G., Hu, S., and Crews, S. T. (1990). The single-minded gene of Drosphila is required for the expression of genes important for the development of CNS midline cells. Cell 63:63-75.
 
Nambu, J.R., Lewis, J.O., Wharton, K.A., and Crews, S.T. (1991). The Drosophila single-minded gene encodes a helix-loop-helix protein which acts as a master regulator of CNS midline development. Cell 67: 1157-1167.
 
Kasai, Y., Nambu, J.R., Lieberman, P.M., and Crews, S.T. (1992). Dorsal-ventral patterning in Drosophila: DNA binding of snail protein to the single-minded gene. Proc. Natl. Acad. Sci. USA 89: 3414-3418.
Nambu, J.R., Lewis, J.O., and Crews, S.T. (1993). The development and function of the Drosophila CNS midline cells. Comp. Biochem. Physiol. 104A(3): 399-409.
 
Zhou, L., Hashimi, H., Schwartz, L.M., and Nambu, J.R. (1995). Programmed cell death in the Drosophila central nervous system midline. Cur. Biol. 5:784-790.
 
Nambu, J. R., Chen, W., Su, H., and Crews, S. T. (1996). The Drosophila melanogaster similar bHLH-PAS gene encodes a protein related to human hypoxia-inducible factor 1a and Drosophila single-minded. Gene, 172:249-254.
 
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.
 
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.
 
Zhou, L., Schnitzler, A., Agapite, J., Schwartz, L., Steller, H., and Nambu, J.R. (1997). Cooperative functions of the reaper and head involution defective genes in the programmed cell death of Drosophila CNS midling cells. Proc. Natl. Acad. Sci (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.
 
Ma, Y., Nambu, P.A., Shan, X., Niemitz, E.L., Sackerson, C., Fujioka, M., Goto, T., and Nambu, J.R. (1998). Gene regulatory functions of Drosophila Fish-hook, a high mobility group domaine Sox protein. Mechanisms of Development 73:169-182.
 
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.
 
Mutsuddi, M. and Nambu, J.R. (1998). Neural disease. Drosophila degenerates for a good cause. Current Biology R809-R811.

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.

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.

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.

 

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