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<p>Excitatory amino acid transporters (EAATs; SLC1 family) are expressed in neurons and glial cells and are essential for glutamatergic signaling and neuroprotection in the vertebrate retina. However, lineage-specific genome duplications, especially in teleosts, and <i>eaat</i> gene losses during vertebrate evolution, raise the question of whether retinal EAAT functions are conserved across species. In our study, we combine retinal expression mapping, transgenic reporter assays, and electrophysiological characterization to examine the evolutionary diversification of EAAT expression and function of some key species across different vertebrate clades. The gene loss of <i>eaat6</i> and <i>eaat7</i> in eutherian mammals results in a pronounced shift in retinal expression of <i>eaat1</i> to <i>eaat5</i> when compared to non-therian vertebrates. While in the mouse retina <i>Eaat1</i> (<i>Glast-1</i>) is expressed in Muller glia cells, <i>Eaat2</i> (<i>Glt-1</i>) transcripts are predominantly found in bipolar cells. In contrast to this, Muller glia cells of zebrafish (<i>Danio rerio</i>) predominantly express <i>eaat2a</i> and transcripts for neither of the two zebrafish <i>eaat1</i> paralogs are present in the retina. On the other hand, the predominant neuronal <i>eaat</i> transcripts in the zebrafish retina are <i>eaat2b</i> and <i>eaat7</i>. A transgenic zebrafish line expressing GFP under the control of mouse <i>Eaat1</i> regulatory elements demonstrates that mouse <i>Eaat1</i> cis-regulatory sequences drive neuronal, rather than glial, expression in zebrafish, indicating evolutionary divergence of regulatory logic. Electrophysiological analyses of recombinant EAAT proteins reveal that these expression changes are paralleled by differences in biophysical properties. Glial EAATs display a low ratio of uncoupled anion conductances to glutamate transport currents, consistent with a primary role in glutamate clearance, whereas neuronally expressed EAATs exhibit disproportionately large anion currents, supporting a role in modulating membrane excitability. Taken together, our findings demonstrate that retinal <i>eaat</i> expression patterns and functional specializations have been extensively reshaped during vertebrate evolution, advising caution against a direct extrapolation of mouse retinal glutamate handling to non-mammalian species.</p>

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Evolutionary gene number variation and functional diversification of retinal EAATs are reflected in expression pattern adaptation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • André Lehnherr,
  • Peter Kovermann,
  • Christoph Fahlke,
  • Stephan C. F. Neuhauss,
  • Matthias Gesemann

摘要

Excitatory amino acid transporters (EAATs; SLC1 family) are expressed in neurons and glial cells and are essential for glutamatergic signaling and neuroprotection in the vertebrate retina. However, lineage-specific genome duplications, especially in teleosts, and eaat gene losses during vertebrate evolution, raise the question of whether retinal EAAT functions are conserved across species. In our study, we combine retinal expression mapping, transgenic reporter assays, and electrophysiological characterization to examine the evolutionary diversification of EAAT expression and function of some key species across different vertebrate clades. The gene loss of eaat6 and eaat7 in eutherian mammals results in a pronounced shift in retinal expression of eaat1 to eaat5 when compared to non-therian vertebrates. While in the mouse retina Eaat1 (Glast-1) is expressed in Muller glia cells, Eaat2 (Glt-1) transcripts are predominantly found in bipolar cells. In contrast to this, Muller glia cells of zebrafish (Danio rerio) predominantly express eaat2a and transcripts for neither of the two zebrafish eaat1 paralogs are present in the retina. On the other hand, the predominant neuronal eaat transcripts in the zebrafish retina are eaat2b and eaat7. A transgenic zebrafish line expressing GFP under the control of mouse Eaat1 regulatory elements demonstrates that mouse Eaat1 cis-regulatory sequences drive neuronal, rather than glial, expression in zebrafish, indicating evolutionary divergence of regulatory logic. Electrophysiological analyses of recombinant EAAT proteins reveal that these expression changes are paralleled by differences in biophysical properties. Glial EAATs display a low ratio of uncoupled anion conductances to glutamate transport currents, consistent with a primary role in glutamate clearance, whereas neuronally expressed EAATs exhibit disproportionately large anion currents, supporting a role in modulating membrane excitability. Taken together, our findings demonstrate that retinal eaat expression patterns and functional specializations have been extensively reshaped during vertebrate evolution, advising caution against a direct extrapolation of mouse retinal glutamate handling to non-mammalian species.