Cyst formation in zebrafish

• Applicant: Dr. Albrecht Kramer-Zucker
• Subject Area: Nephrology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 58488057

• Final Report Year: 2018

Final Report Abstract

Polycystic kidney disease is a group of inheritable diseases characterized by cystic degeneration of the kidneys. Cilia play an important role in the mechanism of the disease. Using zebrafish larvae we could demonstrate that the gene families of Nephrophthisis and Bardet-Biedl-Syndrome show many genetic interactions on the level of protein function which explains the broad overlap in phenotype. Multiciliated cells (MCCs) are essential for proper embryonic development in zebrafish. A crucial step during ciliogenesis in MCCs is the association of future basal bodies with the apical plasma membrane, followed by their correct spacing and planar orientation. Taking the advantigae of a second animal model, Xenopus laevis, we could identify the ELMO-DOCK1-Rac1-Ezrin complex as a new module that, by influencing the cortical actin web in MCCs, orchestrates ciliary basal body migration, docking and spacing at the apical cell membrane. Malfunction of the MCCs causes kidney cysts in zebrafish, and pulmonary airway disease in humans. If ELMO-DOCK1-Rac1-Ezrin complex plays a role in renal repair after acute kidney injury, still has to be evaluated. Similarly, the exact mechanism of how Rac1 regulates Ezrin function, its role in human disease, and possible treatment options remain subject-matter of further investigations.

Publications

• Genetic and physical interaction between the NPHP5 and NPHP6 gene products. Hum Mol Genet 2008; 17:3655-62. Erratum in: Hum Mol Genet 2009; 18:4226
  Schäfer T, Pütz M, Lienkamp S, Ganner A, Bergbreiter A, Ramachandran H, Gieloff V, Gerner M, Mattonet C, Czarnecki PG, Sayer JA, Otto EA, Hildebrandt F, Kramer-Zucker A, Walz G
  
• Nephrocystin-4 is required for pronephric duct-dependent cloaca formation in zebrafish. Hum Mol Genet. 2011; 20(16):3119-28
  Slanchev K, Pütz M, Schmitt A, Kramer-Zucker A, Walz G
  
• A complex of BBS1 and NPHP7 is required for cilia motility in zebrafish. PLoS One. 2013 Sep 12; 8(9):e72549
  Kim YH, Epting D, Slanchev K, Engel C, Walz G, Kramer-Zucker A
  
• ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet. 2013; 45(8):951-6
  Hoff S, Halbritter J, Epting D, Frank V, Nguyen TM, van Reeuwijk J, Boehlke C, Schell C, Yasunaga T, Helmstädter M, Mergen M, Filhol E, Boldt K, Horn N, Ueffing M, Otto EA, Eisenberger T, Elting MW, van Wijk JA, Bockenhauer D, Sebire NJ, Rittig S, Vyberg M, Ring T, Pohl M, Pape L, Neuhaus TJ, Elshakhs NA, Koon SJ, Harris PC, Grahammer F, Huber TB, Kuehn EW, Kramer-Zucker A, Bolz HJ, Roepman R, Saunier S, Walz G, Hildebrandt F, Bergmann C, Lienkamp SS
  
• Interaction with the Bardet-Biedl Gene Product TRIM32/BBS11 Modifies the Half-Life and Localization of Glis2/NPHP7. J Biol Chem. 2014; 289(12):8390-401
  Ramachandran H, Schäfer T, Kim Y, Herfurth K, Hoff S, Lienkamp SS, Kramer-Zucker A, Walz G
  
• The Rac1 regulator ELMO controls basal body migration and docking in multiciliated cells through interaction with Ezrin. Development. 2015 Jan 1; 142(1):174-84. Erratum in: Development. 2015 Apr 15;142(8):1553
  Epting D, Slanchev K, Boehlke C, Hoff S, Loges NT, Yasunaga T, Indorf L, Nestel S, Lienkamp SS, Omran H, Kuehn EW, Ronneberger O, Walz G, Kramer-Zucker A