Regulation of Neuron Development by a Nuclear Receptor

Muhlenberg College, Allentown PA

Investigators

Abstract

During nervous system development, neurons are generated from embryonic precursor cells. Subsequently, neurons diverge from each other to create myriad neuronal cell types, each with distinct identities. For example, neurons involved in smell are quite different from those that function in regulation of breathing. Thus neurons come to differ from each other in terms of physiology, neurotransmitter expression, axonal morphology, and synaptic connectivity. The mechanisms by which individual neuron identities are specified are not well understood, but are known to involve the activity of proteins that "turn on" and "off" other genes. The objective of this research is to increase understanding of the process of specification of neuron identity by studying the fax-1 gene of the nematode Caenorhabditis elegans. fax-1 encodes a nuclear hormone receptor protein, the type of protein that turns on and off other genes. When the fax-1 gene is mutated, some neurons don't form properly. The nematode is an excellent model system in which to study the mechanisms of nervous system development by virtue of its well-characterized 302-cell nervous system and its virtually completely-sequenced genome. Other molecules that function in invertebrate nervous system development have been shown to perform similar functions in vertebrates. A human nuclear hormone receptor related to fax-1 has been identified and shown to be expressed specifically in human photoreceptor cells. Therefore, a study of fax-1 in C. elegans may inform on the function of a human nervous system-specific gene. This study will investigate the molecular mechanism of specification of neuron identity by identifying some of the genes that are regulated by fax-1. First, the DNA sequence to which the FAX-1 protein binds will be defined. Second, the genes that are regulated by fax-1 will be identified through two major experimental approaches. In one approach specific DNA fragments to which the FAX-1 protein binds are identified in a yeast-based system. In a second approach, genes that are turned on or off in response to fax-1 are identified using state-of-the-art DNA microarray technology. This research will advance our knowledge about the basic biological question of how different neuronal cell types are specified and may define a new developmental mechanism that is conserved from nematodes to humans. An additional major goal is to advance undergraduate education by giving students primary roles in a molecular genetic research project that involves both "classical" recombinant DNA and current genomic technologies.