Studying neuronal development in <i>Caenorhabditis elegans</i>: The role of the ARX homolog, <i>alr-1</i>
Precise neuronal development is essential for the formation of a functional nervous system and expression of appropriate behaviors. Neurons must be generated in the correct numbers and with the correct subtype-specific characteristics. Although development of the nervous system has been studied for decades much remains to be understood about the molecules and signals required. C. elegans provides an excellent model in which to study neuronal development due to its small nervous system, known circuitry and cell lineage. In addition, its full genomic sequence is known and genes can be easily manipulated. Through isolation of mutants, which alter marker expression in specific neuron types, gene networks that regulate the development of various neurons have been identified. For example, LIN-11, a LIM-homeodomain transcription factor, regulates the development of the AWA and ASG chemosensory neurons. Within AWA neurons, LIN-11 initiates expression of ODR-7, a nuclear hormone receptor transcription factor regulating all their known differentiated characteristics. UNC-130, a forkhead transcription factor, acts to regulate the correct asymmetric division of the AWA/ASG precursors. However, additional genes that act with lin-11 and unc-130 to differentially specify AWA and ASG neurons are unknown. To address these questions, I isolated animals with defects in the development of the AWA neurons. One of the genes isolated was alr-1, a homolog of the Drosophila Aristaless homeobox gene. Characterization of alr-1, showed it to be required for the specification of both AWA and ASG neurons. In addition, I showed that ALR-1 is required for the differentiation of a GABAergic motorneuron subset. Epistasis analysis placed ALR-1 in genetic pathways with genes previously known to be required for the development of these neuron types including lin-11 and unc-130. Interestingly, ARX the vertebrate homolog of alr-1 has been shown to function in conserved genetic networks to regulate the development of GABAergic and other neuron types. Mutations in ARX have been implicated in mental retardation in humans. Thus, studying the development of the nervous system in C. elegans may provide insights into the mechanisms by which conserved genes function in development and disease.
0307: Molecular biology