The eEF1〈-2 gene (S1) encodes a tissue-specific isoform of peptide elongation factor-1A (eEF1A-1); its mRNA is expressed only in brain, heart, and skeletal muscle, tissues dominated by terminally differentiated, long-lived cells. Homozygous mutant mice exhibit muscle wasting and neurodegeneration, resulting in death around postnatal day 28. eEF1〈-2/S1 protein shares 92% identity with eEF1A-1; because specific antibodies for each were not available previously, it was difficult to study the developmental expression patterns of these two peptide elongation factors 1A in wasted and wildtype mice. We generated a peptide-derived antiserum that recognizes the eEF1〈-2/S1 isoform and does not cross-react with eEF1A-1. We characterized the expression profiles of eEF1A-1 and eEF1A-2/S1 during development in wild-type (؉/؉), heterozygous (؉/wst), and homozygous (wst/wst) mice. In wild-type and heterozygous animals, eEF1A-2/S1 protein is present only in brain, heart, and muscle; the onset of its expression coincides with a concomitant decrease in the eEF1A-1 protein level. In wasted mutant tissues, even though eEF1A-2/S1 protein is absent, the scheduled decline of eEF1A-1 occurs nonetheless during postnatal development, as it does in wild-type counterparts. In the brain of adult wild-type mice, the eEF1A-2/S1 isoform is localized in neurons, whereas eEF1A-1 is found in non-neuronal cells. In neurons prior to postnatal day 7, eEF1A-1 is the major isoform, but it is later replaced by eEF1A-2/S1, which by postnatal day 14 is the only isoform present. The postdevelopmental appearance of eEF1A-2/S1 protein and the decline in eEF1A-1 expression in brain, heart, and muscle suggest that eEF1A-2/S1 is the adult form of peptide elongation factor, whereas its sister is the embryonic isoform, in these tissues. The absence of eEF1A-2/S1, as well as the on-schedule development-dependent disappearance of its sister gene, eEF1A, in wst/ wst mice may result in loss of protein synthesis ability, which may account for the numerous defects and ultimate fatality seen in these mice.Peptide elongation factor-1A (eEF1A-1) 1 is an abundant protein, once thought to be ubiquitously expressed; its major role is to mediate the transfer of charged aminoacyl-tRNA to the A site of the ribosome during peptide elongation. We have previously shown that the mRNA expression of this gene declines in rat brain, heart, and skeletal muscle during development (1, 2), to the extent that in adult skeletal muscle, there is an almost complete loss of eEF1A-1 mRNA expression; a sister gene, eEF1A-2/S1, is expressed instead (3). Furthermore, in contrast to the ubiquitous expression of eEF1A-1 in many cell types, eEF1A-2/S1 expression is limited to the terminally differentiated cells of the brain, heart, and skeletal muscle (3, 4).Recent evidence suggests that eEF1A-2/S1 is an alternative peptide elongation factor-1A for neurons and myocytes, because the amino acid homology between them is 92% (5, 6), and eEF1A-2/S1 can perform peptide elongation in vitro (7). The absence ...