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The Journal of Neuroscience, January 1, 2002, 22(1):167-175

Synaptic Activity-Induced Conversion of Intronic to Exonic Sequence in Homer 1 Immediate Early Gene Expression

Daniele Bottai¹, John F. Guzowski², Martin K. Schwarz¹, Shin H. Kang³, Bo Xiao³, Anthony Lanahan³, Paul F. Worley³, and Peter H. Seeburg¹

¹ Department of Molecular Neurobiology, Max-Planck Institute for Medical Research, 69120 Heidelberg, Germany, ² Arizona Research Laboratories, Division of Neural Systems, Memory, and Aging, University of Arizona, Tucson, Arizona 85724-5115, and ³ Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205

Three Homer genes regulate the activity of metabotropic glutamate receptors mGluR1a and mGluR5 and their coupling to releasable intracellular Ca²⁺ pools and ion channels. Only the Homer 1 gene evolved bimodal expression of constitutive (Homer 1b and c) and immediate early gene (IEG) products (Homer 1a and Ania 3). The IEG forms compete functionally with the constitutive Homer proteins. The complex expression of the Homer 1 gene, unique for IEGs, focused our attention on the gene organization. In contrast to most IEGs, which have genes that are <5 kb, the Homer 1 gene was found to span ~100 kb. The constitutive Homer 1b/c forms are encoded by exons 1-10, whereas the IEG forms are encoded by exons 1-5 and parts of intron 5. RNase protection demonstrated a >10-fold activity-dependent increase in mRNA levels exclusively for the IEG forms. Moreover, fluorescent in situ hybridization documented that new primary Homer 1 transcripts are induced in neuronal nuclei within a few minutes after seizure, typical of IEGs, and that Homer 1b-specific exons are excluded from the activity-induced transcripts. Thus, at the resting state of the neurons, the entire gene is constitutively transcribed at low levels to yield Homer 1b/c transcripts. Neuronal activity sharply increases the rate of transcription initiation, with most transcripts now ending within the central intron. These coordinate transcriptional events rapidly convert a constitutive gene to an IEG and regulate the expression of functionally different Homer 1 proteins.

Key words: immediate early gene; induced neuronal activity; activity-dependent switch of intron to exon; alternative splicing; alternative transcriptional termination; RNase protection; fluorescent in situ hybridization

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Copyright © 2002 Society for Neuroscience  0270-6474/02/221167-09$05.00/0

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