genetic and molecular analysis of visual system development in Drosophila
	Douglas R. Kankel, Ph.D. Professor of Molecular, Cellular & Developmental Biology Email: douglas.kankel@yale.edu Room: KBT 111A Phone: (203) 432-3532 / (203) 432-3533

The work in this laboratory seeks a definition of the molecular mechanisms which underlie the assembly of the central nervous system. To this end we have focused on a study of the development of the visual system in the fly Drosophila melanogaster. We have chosen the visual system for a number of reasons, chief among them being those of its nearly crystalline structure and the relative ease with which one may isolate mutations on the basis of either structural or behavioral abnormalities. There are presently three broad areas under investigation.

In the first we aim at the identification and analysis of those genetic loci which play a prominent role in the development of the imaginal visual system. We are particularly interested in those loci which have a significant impact on the development and maintenance of the connectivity of the photoreceptors of the compound eyes with the neurons of the optic lobes, the main processing centers for visual input within the CNS. We are currently working most extensively with a locus designated l(1)optic ganglion reduced (ogre) which was originally identified on the basis of the isolation of a mutant with aberrant visuo-motor behavior. We have shown this mutant to be rather specifically associated with the abnormal development of the optic lobes during the larval postembryonic developmental period; the subsequent isolation of additional mutations at this locus has yielded a series of lethal alleles which, like the initial viable one, have profound abnormalities in optic lobe development but also have aberrant development in a number of other subsets of the CNS. We hypothesize that this locus is intimately involved in that portion of the CNS which is imaginal-specific, i.e., developed during the larval stage but plays no functional role until adulthood. This locus is now undergoing extensive molecular analysis in hopes of unraveling the mechanism/s by which its gene product/s bring about the observed phenotypes.

A second area of investigation seeks to understand the role of neurotransmitters and neurotransmitter metabolism, in general, in the initial assembly and the subsequent maintenance of structure of the CNS. This work is based on our observation that genetic mosaics which carry clones of cells which are homozygous for null-activity variants at either the Cha or Ace loci which encode the synthetic (choline acetyltransferase) and degradative (acetylcholinesterase) enzymes, respectively, for acetylcholine invariably have pronounced structural abnormalities within the CNS in all enzyme deficient tissues. We have recently demonstrated that these abnormalities are a consequence not of aberrant development, but of a failure of the system to maintain its normal structure post- developmentally. We are currently seeking to understand the molecular basis of this phenomenon and are attempting to determine whether this obtains for other transmitters as well, with a major additional focus on glutamate, a known excitatory transmitter at nerve-muscle junctions.

The third area ultimately seeks to address the role of cell-surface glycoproteins as important informational molecules in the cell interactions that almost certainly occur during the building of the visual system in Drosophila. We have undertaken a biochemical characterization of N-linked glycoprotein biosynthesis in this organism and have isolated a number of mutants which affect this pathway. We have a preliminary characterization of these mutants genetically and biochemically and have begun to assess their impact via genetic mosaics on the normal projection of axons and the patterns of connectivity within the developing visual system of cells which can no longer synthesize the normal spectrum of surface glycoproteins.

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