The amino acid transporter Slc7a5 regulates the mTOR pathway and is required for granule cell development
| Autor: | Jennie C. Holmberg, Aidan M. Sokolov, David M. Feliciano |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
AcademicSubjects/SCI01140 Subventricular zone Embryonic Development Biology Large Neutral Amino Acid-Transporter 1 Small hairpin RNA 03 medical and health sciences Mice 0302 clinical medicine Neural Stem Cells Seizures Genetics medicine Animals Humans Amino acid transporter Amino Acids Molecular Biology Genetics (clinical) PI3K/AKT/mTOR pathway Sequence Deletion Neurons Gene knockdown TOR Serine-Threonine Kinases General Medicine Granule cell Olfactory Bulb Neural stem cell Cell biology Electrophysiological Phenomena 030104 developmental biology medicine.anatomical_structure Blood-Brain Barrier Microcephaly General Article Neural development 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 |
| Popis: | Pathogenic mutations in the solute carrier family 7 member 5 (SLC7A5) gene, which encodes an amino acid transporter cause microcephaly and seizures, yet the mechanisms responsible for these phenotypes are unclear. Models have demonstrated that Slc7a5 deletion is embryonic lethal and that these embryos lack a fully formed telencephalon. This phenotype is similar to that of mammalian target of rapamycin (mTOR) protein kinase deletion or mTOR inhibition. Notably, in many cells, Slc7a5 import of amino acids is required to maintain mTOR activity. Slc7a5 is present within neurogenic regions during embryogenesis, is found in cultured neurons and can modulate neuronal electrophysiological properties. However, Slc7a5 is also highly expressed within endothelial cells of the blood–brain barrier where removal in conditional mice leads to severe behavioral defects and non-cell autonomous changes in neurons. Therefore, the extent that neural Slc7a5 is required for development is unclear. Here, subventricular zone neural stem cells that generate olfactory bulb granule cell neurons were electroporated with SLC7A5 or Slc7a5 short hairpin RNA encoding plasmids. Although early phases of neural development were unaltered, Slc7a5 knockdown effected late phases of GC dendrite maturation and survival. Slc7a5 knockdown also decreased mTOR pathway activity. Ras homolog enriched in brain, an mTOR activator, rescued the effect of Slc7a5 knockdown on mTOR pathway activity and dendrite arbors. The data presented here demonstrate that Slc7a5 is required for GC mTOR pathway activity, maturation and survival, which may help explain why Slc7a5 mutations prevent normal brain development and function. |
| Databáze: | OpenAIRE |
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