SLC7 family transporters control the establishment of left-right asymmetry during organogenesis in medaka by activating mTOR signaling.
The precise government of the left-right (LR) specification of an organ is an essential aspect of its morphogenesis. Multiple signaling cascades have been implicated in the establishment of vertebrate LR asymmetry. Recently, mTOR signaling was found to critically regulate the development of LR asymmetry in zebrafish. However, the upstream factor(s) that activate mTOR signaling in the context of LR specification are as yet unknown. In this study, we identify the SLC7 amino acid transporters Slc7a7 and Slc7a8 as novel regulators of LR asymmetry development in the small fish medaka. Knockdown of Slc7a7 and/or Slc7a8 in medaka embryos disrupted LR organ asymmetries. Depletion of Slc7a7 hindered left-sided expression of the southpaw (spaw) gene, which is responsible for LR axis determination. Work at the cellular level revealed that Slc7a7 coordinates ciliogenesis in the epithelium of Kupffer's vesicle and thereby the generation of the nodal fluid flow required for LR asymmetry. Interestingly, knockdown of Slc7a7 depressed mTOR signaling activity in medaka embryos. Treatment with rapamycin, an inhibitor of mTOR signaling, together with Slc7a7 knockdown synergistically perturbed spaw expression, indicating an interaction between Slc7a7 and mTOR signaling affecting gene expression required for LR specification. Taken together, our results demonstrate that Slc7a7 governs the regulation of LR asymmetry development via the activation of mTOR signaling.
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Yoichi
Y
Asaoka
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Yoko
Y
Nagai
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Misako
M
Namae
Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Makoto
M
Furutani-Seiki
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address: nishina.dbio@mri.tmd.ac.jp.
Hiroshi
H
Nishina
D027241:Amino Acid Transport System y+L; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D027301:Fusion Regulatory Protein 1, Light Chains / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D038081:Organogenesis / Q000502:physiology*; D009990:Oryzias / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D027241:Amino Acid Transport System y+L; D027301:Fusion Regulatory Protein 1, Light Chains; C421261:SLC7A7 protein, human; D058570:TOR Serine-Threonine Kinases
Ciliogenesis; Left-right asymmetry; Medaka; Nodal flow; SLC7 transporter; mTOR signaling