The nervous system precisely coordinates neuronal fate and morphology to establish functional neural circuits during development. For example, motorneurons can be classified based on common patterns of axonal growth as well as by transcription factor expression profiles. Motor axons of distinct motorneuron subtypes make common guidance decisions as they navigate toward their muscle targets, suggesting that motorneuron subtypes express related sets of receptor and signaling molecules. Despite this elegant model, little is known about the transcriptional mechanisms acting in populations of neurons to produce characteristic axonal trajectories.

We use the fruit fly Drosophila to understand fundamental biological mechanisms guiding the generation of functional neuronal classes. In addition to the well-known genetic and experimental advantages of Drosophila the relatively low number of neurons, the detailed description of neural stem cell lineages, and the wealth of molecular markers permit the analysis of neuronal fate acquisition at the level of the single neuron. Despite its simplicity, the vast majority of the molecules implicated in Drosophila CNS development are functionally conserved in more complex vertebrate systems.

We have characterized several conserved homeodomain transcription factors required for the development of specific motorneuron subtypes. Drosophila homeodomain proteins Hb9 and Nk6 function in parallel to specify the fate of motorneurons that project their axons to ventral muscles. While nk6 acts redundantly with hb9 to regulate motorneuron fate, nk6 has a singular requirement in promoting axon growth and regulates the expression of a key determinant of synaptic target selection in this class of neurons. Thus, nk6 plays a key role in linking neuronal subtype identity to neuronal morphology and connectivity.

To identify novel determinants of motorneuron identity, we have conducted a large-scale gene misexpression screen. We have identified 95 genes that yield specific defects in neuronal fate or axonal pathfinding when they are misexpressed in post-mitotic neurons. These lines represent a rich resource from which to identify genes critical for neuronal differentiation. They encode a molecularly diverse set of proteins functioning in multiple aspects of neuronal development: including likely transcription factors, adaptor proteins, receptor molecules, and cytoskeletal proteins-as well as several molecules of novel structure. We have initiated a functional characterization of the role of a subset of these proteins in neuronal specification and differentiation.

1. Broihier HT, Kuzin A, Zhu Y, Odenwald W, Skeath JB. (2004)
   Drosophila homeodomain protein Nkx6 coordinates motoneuron subtype identity and axonogenesis. Development. 2004 Nov; 131(21):5233-5242. 2004/09/29 [aheadofprint].
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2. Van Doren M, Mathews WR, Samuels M, Moore LA, Broihier HT, Lehmann R. (2003)
   fear of intimacy encodes a novel transmembrane protein required for gonad morphogenesis in Drosophila. Development. 2003 Jun; 130(11):2355-2364.
   
3. Stein JA, Broihier HT, Moore LA, Lehmann R. (2002)
   Slow as molasses is required for polarized membrane growth and germ cell migration in Drosophila. Development. 2002 Aug; 129(16):3925-3934.
   
4. Broihier HT, Skeath JB. (2002)
   Drosophila homeodomain protein dHb9 directs neuronal fate via crossrepressive and cell-nonautonomous mechanisms. Neuron. 2002 Jul 3; 35(1):39-50.
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