Long-range interactions in neuronal gene expression:: Evidence from gene targeting in the GABAA receptor β2-α6-α1-γ2 subunit gene cluster

Clustering of GABA(A) receptor alpha 1, alpha 6, beta 2, and gamma 2 subunit genes on mouse chromosome 11/human chromosome 5 may have functional significance for coordinating expression patterns, but until now there has been no evidence for cross-talk between the genes. However, altering the structure of the alpha 6 gene, specifically expressed in the cerebellum, with neomycin gene insertions in two different experiments unexpectedly reduced the expression of the widespread alpha 1 and beta 2 genes in the forebrain. There were corresponding reductions in the levels of alpha 1 and beta 2 subunit proteins and in autoradiographic ligand binding densities to GABA(A) receptors in the forebrain of alpha 6-/- mice. The gamma 2 mRNA level was not changed, nor were beta 3 and delta mRNAs. The data suggest that elements in the neo gene may have an influence over long distances in the GABA(A) subunit gene complex on as yet undefined structures coordinating the expression of the alpha 1 and beta 2 genes.