Complex control of GABA(a) receptor subunit mRNA expression

Variation, covariation, and genetic regulation

Megan Mulligan, Xusheng Wang, Adrienne L. Adler, Khyobeni Mozhui, Lu Lu, Robert Williams

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents-C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel-Gabra1, Gabrb2, and Gabrg2-and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3′ UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal), even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer 4-100 fold differences in mRNA levels.

Original languageEnglish (US)
Article numbere34586
JournalPloS one
Volume7
Issue number4
DOIs
StatePublished - Apr 10 2012

Fingerprint

GABA Receptors
gamma-Aminobutyric Acid
Brain
Chromosomes, Human, Pair 5
Messenger RNA
receptors
loci
Genetic Loci
3' Untranslated Regions
GABA-A Receptors
Chromosomes
Sequence Homology
Synaptic Transmission
brain
Hippocampus
Buffers
Anxiety
Genes
gamma-aminobutyric acid
mice

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Complex control of GABA(a) receptor subunit mRNA expression : Variation, covariation, and genetic regulation. / Mulligan, Megan; Wang, Xusheng; Adler, Adrienne L.; Mozhui, Khyobeni; Lu, Lu; Williams, Robert.

In: PloS one, Vol. 7, No. 4, e34586, 10.04.2012.

Research output: Contribution to journalArticle

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