The development of a functional nervous system requires the specification and precise organization of a large number of neural cell types. We are interested in how cell diversity in the nervous system is generated. In particular, we are investigating the mechanisms by which neural cells acquire glial vs. neuronal cell fates, using classical and molecular genetic approaches in the fruit fly Drosophila.

Our studies have focused on the glial cells missing (gcm)gene, a master regulator of glial cell fate in Drosophila. gcm encodes a novel nuclear protein that is transiently expressed early in the development of nearly all glia in Drosophila. In the presence of GCM protein, presumptive neurons become glia, while in its absence, presumptive glia become neurons. The identification of mammalian homologs of GCM has revealed a highly conserved 153 amino-acid domain. DNA-binding activity maps to this domain, suggesting that GCM is a novel transcription factor. While the role of GCM homologs in mammalian development is not yet clear, expression of mammalian GCM1 protein in Drosophila causes neuron to glia transformations, indicating that GCM1 shares conserved regulatory capabilities. These regulatory capabilities are likely to be confined to the GCM-domain.

We have demonstrated that glial cell determination is controlled by the precise regulation of gcm expression and activity in neural progenitors. Because gcm is transiently expressed, gcm can only initiate glial cell differentiation. Downstream genes must accomplish glial differentiation and maintenance of glial cell fate. To understand how glial cell development is controlled, we aim to understand how gcm transcription is activated in different neural lineages, what factors regulate GCM activity, and what are the downstream genes that carry out glial cell differentiation.

We are currently pursuing these aims through the following projects: 1) the molecular genetic characterization of cis-regulatory DNA elements controlling gcm transcription; 2) the identification and characterization proteins that modulate GCM activity; 3) the molecular genetic characterization of cis-regulatory elements of the candidate gcm-target gene, repo; and, 4) a systematic classical Drosophila mutagenesis screen for genes that modify the expression and pattern of REPO protein, a glial specific marker that is directly regulated by gcm.