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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH001426-05
Application #
6185756
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Program Officer
Goldschmidts, Walter L
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
2000-09-01
Budget End
2001-07-31
Support Year
5
Fiscal Year
2000
Total Cost
$147,053
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Chiesa, R; Pestronk, A; Schmidt, R E et al. (2001) Primary myopathy and accumulation of PrPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation. Neurobiol Dis 8:279-88
Tourtellotte, W G; Keller-Peck, C; Milbrandt, J et al. (2001) The transcription factor Egr3 modulates sensory axon-myotube interactions during muscle spindle morphogenesis. Dev Biol 232:388-99
Tourtellotte, W G; Nagarajan, R; Bartke, A et al. (2000) Functional compensation by Egr4 in Egr1-dependent luteinizing hormone regulation and Leydig cell steroidogenesis. Mol Cell Biol 20:5261-8
Tourtellotte, W G; Nagarajan, R; Auyeung, A et al. (1999) Infertility associated with incomplete spermatogenic arrest and oligozoospermia in Egr4-deficient mice. Development 126:5061-71
Tourtellotte, W G; Milbrandt, J (1998) Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3. Nat Genet 20:87-91
Brown, P (1993) Psychiatric intake as a mystery story. Cult Med Psychiatry 17:255-80
Rubinsky, H J; Hoon, P W; Eckerman, D A et al. (1985) Groin skin temperature: testing the validity of a relatively unobtrusive physiological measure of psychosexual arousal. Psychophysiology 22:488-92