Molecular neurotoxicology of trimethyltin: identification of stannin, a novel protein expressed in trimethyltin-sensitive cells.
The molecular basis of selective vulnerability of specific neuronal populations to neurotoxicants remains a key focus in neurotoxicology. Trimethyltin (TMT) selectively damages neurons in rodent and human central nervous system after a single exposure. By coupling subtractive hybridization with molecular cloning techniques, we isolated a cDNA specifically localized in TMT-sensitive cells. This 2.9-kilobase cDNA encodes a putative 10-kDa peptide of 88 amino acids, termed "stannin." In immunocytochemical experiments, antisera raised against the amino terminus of stannin exhibited strong immunoreactivity in TMT-sensitive neurons in the hippocampus and entorhinal cortex, areas previously identified by in situ hybridization. Northern blot and in situ hybridization experiments detected a 3.0-kilobase stannin mRNA in brain, spleen, and kidney; expression occurred as early as embryonic day 15 in rat brain and thymus. In situ hybridization in human hippocampus demonstrated a stannin mRNA in pyramidal and dentate gyrus neurons. High stringency Southern blot analysis of genomic DNA identified stannin homologs in rabbit, Drosophila, and human. These findings indicate that stannin is present in TMT-sensitive cells and may play a role in the selective toxicity of organotin compounds.
Toggas
S M
SM
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey 17033.
Krady
J K
JK
Billingsley
M L
ML
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D004247:DNA; D004926:Escherichia coli / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics*; D010957:Plasmids; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D014298:Trimethyltin Compounds / Q000633:toxicity*
D009479:Neuropeptides; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014298:Trimethyltin Compounds; C046488:trimethyltin; C075692:stannin; D004247:DNA