Complex nervous system processes involving neurotransmitter release and membrane depolarization, or neurotrophin/membrane receptor interactions, exert their control by activating cellular signal transduction pathways that effect long-term phenotypic changes by altering prevailing patterns of gene expression. Two general classes of genes are considered to be coupled to neuron membrane receptor activation, namely, early and rapidly transient gene activation (immediate early genes; IEGs) and late response genes. The Egr gene family of IEGs has been consistently implicated in trans-synaptic activation and neurotrophin/membrane receptor interactions, and consists of four known transcription factors that include egr1 (also known as NGFI-A, zif/268, and Krox24), egr2 (also known as Krox20), egr3 and egr4 (also known as NGFI-C and pAT133). A variety of correlative studies have implicated their function in an astounding number of cellular processes as diverse as cell proliferation, lymphocyte activation and apoptosis, neuronal synaptic activity, long-term synaptic potentiation (LTP), neuronal plasticity, neuronal kindling, and circadian rhythm generation. Using gene targeting strategies to study mice having loss-of-function mutations for each gene family member, this research program will focus on their essential functions in the developing and adult mammalian nervous system. As the expression of these genes is extensively colocalized in neurons throughout the nervous system, by studying mice with polygenic-loss-of function mutations (i.e., mice having two or more Egr gene mutations), their potential cooperative/redundant interactions will be examined in the nervous system. Specifically, their roles in mediating neurotrophin signaling involving neuron survival and differentiation will be central areas of active investigation during this research program. Additionally, by examining mice with multiple Egr gene mutations, differential expression analysis will be used to identify down-stream target genes regulated by this family of transcription factors. The postulated central nervous system functions of these genes are potentially highly relevant to learning and memory mechanisms as well as neurodegenerative diseases and dementia. Their activation has been specifically associated with pharmacologically altered dopaminergic neurotransmission in basal ganglia, raising the possibility that they may play a role in cognitive and/or motor impairments associated with a variety of neuropsychiatric illnesses. Moreover, the roles that these genes may play in mediating some aspects of neurotrophin-mediated neuron survival and differentiation is germaine, as these processes are likely to be central to mechanisms involving cell death and aberrant plasticity responses associated with intractable epilepsy and neural kindling, as well as to neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's diseases. Finally, these genes may play a role in long-term synaptic potentiation and structural plasticity mechanisms, and may therefore be relevant to normal learning and memory processing.
