TY - JOUR
T1 - Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression
AU - Bottai, Daniele
AU - Guzowski, John F.
AU - Schwarz, Martin K.
AU - Kang, Shin H.
AU - Xiao, Bo
AU - Lanahan, Anthony
AU - Worley, Paul F.
AU - Seeburg, Peter H.
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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.
AB - 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.
KW - Activity-dependent switch of intron to exon
KW - Alternative splicing
KW - Alternative transcriptional termination
KW - Fluorescent in situ hybridization
KW - Immediate early gene
KW - Induced neuronal activity
KW - RNase protection
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U2 - 10.1523/jneurosci.22-01-00167.2002
DO - 10.1523/jneurosci.22-01-00167.2002
M3 - Article
C2 - 11756499
AN - SCOPUS:0036137945
SN - 0270-6474
VL - 22
SP - 167
EP - 175
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 1
ER -