The focus of the lab is the study of the molecular mechanisms that lead to the generation of specific neural circuits in the brain, which in turn subserve specific behaviors. We are interested in the developmental aspect of neural circuit generation as well as later aspects of maintenance and modification of neural circuits, which presumably are the basis of learning and memory processes. Due to the complexity of the vertebrate brain, we use the much simpler nervous system of the nematode C.elegans as a model system. The completely sequenced genome of C.elegans as well as its amenability to classical genetic methods allow the identification of molecules that are required for the neural differentiation and the generation of specific neural circuits. We have focused our interests on 4 different areas, each of which constitutes an important aspect in the development and functioning of neural circuits.
1) Neuronal patterning: Here, we focus on studying a particular exciting step of neural development, the induction of left/right bilateral asymmetry in the brain. We have identified a homeobox gene that is asymmetrically expressed in the brain of C.elegans and have conducted mutant screens for genes that are required to establish this asymmetry. We have identified the molecular nature of these genes and uncovered a novel signaling pathway.
2) Neuronal differentiation: We have identified a set of putative target genes of a homeobox gene, ttx-3, which we had previously shown to be required for terminal differentiation of an interneuron class in the brain of C.elegans. We are investigating the function of these target genes, one of which is a cell-surface bound protein related to a human disease gene, using both forward and reverse genetic approaches. We also dissect the promoters of these target genes in order to identify the target sites for the homeodomain protein and to understand the molecular logic of transcriptional control in the nervous system.
3) Maintenance of neuronal features: In a reverse genetic approach, we made use of the completed genome sequence of C.elegans and found a novel class of Ig domain proteins that is required for the maintenance of ventral nerve cord organization. We also undertook genetic screens to identify molecules that are required for retrograde signaling from a target cell (muscle or neuron) to its presynaptic neuron target to ensure the maintenance of an intact neuronal morphology.
4) Behavior: The above mentioned research areas deal with aspects of neural circuit development and maintenance, but not with function per se. Several of the target genes that we identified for the homeobox gene ttx-3 are excellent candidates for subserving specific roles in neural circuit functioning and possibly plasticity. We have established a simple behavioral assay to test this possibility.
Altun-Gultekin, Z., Andachi, Y., Tsalik, E., Pilgrim, D., Kohara, Y. and Hobert, O. (2001) "A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23 controls cell fate specification of a defined interneuron class in C . elegans", Development 128, 1951-1969.
Hobert, O., and Westphal, H. (2000) "Function of LIM homeobox genes", Trends Genet. 16, 75-83.
Hobert, O. and Ruvkun, G. (1999) "Pax genes in Caenorhabditis elegans: A new twist", TrendsGenet. 15, 214-216.
Hobert, O., Tessmar, K. and Ruvkun, G. (1999) "The C. elegans lim-6 LIM homeobox gene regulates neurite outgrowth and function of particular GABAergic neurons ", Development126, 1547-1562.
Hobert, O., Moerman, D.G., Clark, K.A., Beckerle, M.C. and Ruvkun, G. (1999) "A conserved LIM protein that affects muscular adherens junction integrity and mechanosensory function in C.elegans ",J. Cell Biol. 144, 45-57.
Hobert, O., D'Alberti, T, Liu, Y. and Ruvkun, G. (1998) "Control of neural development and function in a thermoregulatory network by the LIM homeobox gene lin-11", J.Neurosci. 18, 2084-2096.
Ruvkun, G. and Hobert, O. (1998) "The taxonomy of developmental control in Caenorhabditis elegans", Science 282, 2033-2041.
Hobert, O., Mori, I., Yamashita, Y., Honda, H, Ohshima, Y., Liu, Y. and Ruvkun, G. (1997) "Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene", Neuron 19, 345-357.