The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm
Charlotte D Koopman, Jessica De Angelis, Swati P Iyer, Arie O Verkerk, Jason Da Silva, Geza Berecki, Angela Jeanes, Gregory J Baillie, Scott Paterson, Veronica Uribe, Ophelia Ehrlich, Samuel D Robinson, Laurence Garric, Steven Petrou, Cas Simons, Irina Vetter, Benjamin M Hogan, Teun P de Boer, Jeroen Bakkers, Kelly A Smith
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2021
The establishment of cardiac function in the developing embryo is essential to ensure blood flow and, therefore, growth and survival of the animal. The molecular mechanisms controlling normal cardiac rhythm remain to be fully elucidated. From a forward genetic screen, we identified a unique mutant, grime, that displayed a specific cardiac arrhythmia phenotype. We show that loss-of-function mutations in tmem161b are responsible for the phenotype, identifying Tmem161b as a regulator of cardiac rhythm in zebrafish. To examine the evolutionary conservation of this function, we generated knockout mice for Tmem161b. Tmem161b knockout mice are neonatal lethal and cardiomyocytes exhibit arrhythmic c..View full abstract
Awarded by NIH
This work was supported by research grants from the Australian Research Council and the National Health and Medical Research Council of Australia. Confocal microscopy was performed at the Australian Cancer Research Foundation Dynamic Imaging Centre for Cancer Biology and the Biological Optical Microscopy Platform, with image analysis guidance from Ellie Cho and Shane Cheung. We also acknowledge the support from The Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centres, The Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PREDICT). We thank Y. Onderwater and B. de Jonge for technical assistance and R. Teasdale and J. Vandenberg for helpful discussions. The Tmem161b"czk mouse strain used in this research was generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository (http://www.komp.org).NIH grants to Velocigene at Regeneron Pharaceuticals, Inc. (U01HG004085), and the CSD Consortium (U01HG004080) funded the generation of gene-targeted embryonic stem cells for 8,500 genes in the KOMP program and archived and distributed by the KOMP repository at the University of California, Davis. The Alcama antibody (zn-8) was obtained from the Developmental Studies Hybridoma Bank, created by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH and maintained at the University of Iowa.