Na+/H+ exchanger 1 deficiency alters gene expression in mouse brain.
Na(+)/H(+) exchanger 1 (NHE1) is well known to function as a major regulator of intracellular pH (pH(i)). It is activated by low pH(i) and exchanges extracellular Na(+) for intracellular H(+) to maintain cellular homeostasis. Despite the fact that we now have evidence suggesting other roles for NHE1, there has been no comprehensive study investigating its role as a signaling molecule. Toward this aim, we used in this study NHE1 null mutant mice and cDNA microarrays to investigate the effects of NHE1 on global gene expression in various regions of the brain, e.g., cortex, hippocampus, brain stem-diencephalon, and cerebellum. We found that a total of 35 to 79 genes were up- or downregulated in each brain region, with the majority being downregulated. The effect of NHE1 null mutation on gene expression is region specific, and only 11 genes were changed in all brain regions studied. Further analysis of the cis-regulatory regions of downregulated genes revealed that transcription suppressors, BCL6 and E4BP4, were probable candidates that mediated the inhibitory effect of NHE1 null mutation. One of the genes, MCT-13, was not only downregulated in the NHE1 null mutant brain but also in tissue cultures treated with an NHE1 inhibitor. We conclude that 1) a relatively small number of genes were altered in the NHE1 null mouse brain; 2) the effects of NHE1 null mutation on gene expression are region specific; and 3) several genes implicated in neurodegeneration have altered expression, potentially offering a molecular explanation for the phenotype of the NHE1 null mouse.
Department of Pediatrics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
Dan
D
Zhou
Jin
J
Xue
Orit
O
Gavrialov
Gabriel G
GG
Haddad
D000138:Acidosis / Q000235:genetics; D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D001921:Brain; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D051790:G-Box Binding Factors; D005786:Gene Expression Regulation / Q000235:genetics*; D000860:Hypoxia / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D005810:Multigene Family / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012107:Research Design; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D050976:Basic-Leucine Zipper Transcription Factors; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; D008565:Membrane Proteins; C497441:Nfil3 protein, mouse; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors