Your browser doesn't support javascript.
loading
Mechanism of cystogenesis by Cd79a-driven, conditional mTOR activation in developing mouse nephrons.
Tran Nguyen Truc, Linh; Matsuda, Satoshi; Takenouchi, Akiko; Tran Thuy Huong, Quynh; Kotani, Yui; Miyazaki, Tatsuhiko; Kanda, Hiroaki; Yoshizawa, Katsuhiko; Tsukaguchi, Hiroyasu.
Afiliación
  • Tran Nguyen Truc L; Division of Nephrology, Second Department of Internal Medicine, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.
  • Matsuda S; Department of Cell Signaling, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan. matsudsa@hirakata.kmu.ac.jp.
  • Takenouchi A; Department of Innovative Food Sciences, School of Food Sciences and Nutrition, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
  • Tran Thuy Huong Q; Division of Nephrology, Second Department of Internal Medicine, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.
  • Kotani Y; Department of Cell Signaling, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
  • Miyazaki T; Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan.
  • Kanda H; Department of Diagnostic Pathology, Gifu University Hospital, Gifu, Japan.
  • Yoshizawa K; Department of Pathology, Saitama Cancer Center, Saitama, Japan.
  • Tsukaguchi H; Department of Innovative Food Sciences, School of Food Sciences and Nutrition, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
Sci Rep ; 13(1): 508, 2023 01 10.
Article en En | MEDLINE | ID: mdl-36627370
Polycystic kidney disease (PKD) is a common genetic disorder arising from developmental and postnatal processes. Defects in primary cilia and their signaling (eg, mTOR) underlie the pathogenesis. However, how mTOR regulates tubular integrity remains unclear. The paucity of faithful models has limited our understanding of pathogenesis and, therefore, the refinement of therapeutic targets. To understand the role of mTOR in early cystogenesis, we studied an in-house mouse model, Cd79a-Cre;Tsc1ff. (Cd79a-Tsc1 KO hereafter), recapitulating human autosomal-dominant PKD histology. Cre-mediated Tsc1 depletion driven by the promoter for Cd79a, a known B-cell receptor, activated mTORC1 exclusively along the distal nephron from embryonic day 16 onward. Cysts appeared in the distal nephron at 1 weeks of age and mice developed definite PKD by 4 weeks. Cd79a-Tsc1 KO tubule cells proliferated at a rate comparable to controls after birth but continued to divide even after postnatal day 14 when tubulogenesis is normally completed. Apoptosis occurred only after 9 weeks. During postnatal days 7-11, pre-cystic Cd79a-Tsc1 KO tubule cells showed cilia elongation, aberrant cell intercalation, and mitotic division, suggesting that defective cell planar polarity (PCP) may underlie cystogenesis. mTORC1 was activated in a portion of cyst-lining cells and occasionally even when Tsc1 was not depleted, implying a non-autonomous mechanism. Our results indicate that mTORC1 overactivation in developing distal tubules impairs their postnatal narrowing by disrupting morphogenesis, which orients an actively proliferating cell toward the elongating axis. The interplay between mTOR and cilium signaling, which coordinate cell proliferation with PCP, may be essential for cystogenesis.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Serina-Treonina Quinasas TOR / Enfermedades Renales Poliquísticas Límite: Animals Idioma: En Revista: Sci Rep Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Serina-Treonina Quinasas TOR / Enfermedades Renales Poliquísticas Límite: Animals Idioma: En Revista: Sci Rep Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido