A genetic analysis of left/right asymmetry in Caenorhabditis elegans ASE chemosensory neurons

We study the development of a single pair of morphologically bilaterally symmetric neurons, the functional fates of which are reliant on a complex genetic pathway that we are only beginning to understand. This thesis work began when two graduate students and I embarked on a large-scale forward genetic screen to uncover factors responsible for the functional divergence of the ASE left and right chemosensory neurons in Caenorhabditis elegans that isolated 116 mutants belonging to 25 complementation groups. Two new methods described here, whole genome sequencing and Comparative genome hybridization expedite the identification of causative lesions in EMS generated mutants. Mutants uncovered in this screen are presented including regulatory alleles of previously known genes required for ASE development and a new gene lsy-12. Regulatory mutants of the microRNA lsy-6 and the homeobox transcription factor cog-1 give us a greater understanding of the complex process of controlling gene expression in cell fate decisions. Additionally, I have also cloned and characterized lsy-12, a MYST family histone acetyltransferase that, working in complex with previously identified bromodomain containing protein LIN-49 and newly characterized PHD finger protein LSY-13 is required for both the specification and maintenance of ASEL terminal cell fate, possibly by acting in concert with an additional histone methyltransferases complex. These chromatin modifying complexes, acting as transcriptional coactivators likely act at the level of ASE inducing factors such as the Zn finger transcription factor die-1 to specify and maintain neuronal laterality. The characterization of these mutants and interactions contributes to our overall knowledge of how nervous system development is directed.