Long-range interactions in neuronal gene expression: Evidence from gene targeting in the GABA(A) receptor beta 2-alpha 6-alpha 1-gamma 2 subunit genecluster

Clustering of GABA(A) receptor alpha 1, alpha 6, beta 2, and gamma 2 subuni t genes on mouse chromosome 11/human chromosome 5 may have functional signi ficance for coordinating expression patterns, but until now there has been no evidence for cross-talk between the genes. However, altering the structu re of the alpha 6 gene, specifically expressed in the cerebellum, with neom ycin gene insertions in two different experiments unexpectedly reduced the expression of the widespread alpha 1 and beta 2 genes in the forebrain. The re were corresponding reductions in the levels of alpha 1 and beta 2 subuni t proteins and in autoradiographic ligand binding densities to GABA(A) rece ptors in the forebrain of alpha 6-/- mice. The gamma 2 mRNA level was not c hanged, 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) subun it gene complex on as yet undefined structures coordinating the expression of the alpha 1 and beta 2 genes.