The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm
| Autor: | Benjamin M. Hogan, Angela Jeanes, Steven Petrou, Geza Berecki, Laurence Garric, Ophelia V. Ehrlich, Irina Vetter, Cas Simons, Teun P. de Boer, Charlotte D. Koopman, Samuel D. Robinson, Swati Iyer, Veronica Uribe, Scott Paterson, Jason Da Silva, Arie O. Verkerk, Gregory J. Baillie, Jessica E. De Angelis, Jeroen Bakkers, Kelly A. Smith |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research, Medical Biology, ACS - Amsterdam Cardiovascular Sciences |
| Rok vydání: | 2021 |
| Předmět: |
Periodicity
Embryo Nonmammalian Mouse Forward genetics Arrhythmias Lethal Animals Genetically Modified Mice Myocyte Developmental Arrhythmias Cardiac/genetics Zebrafish Conserved Sequence Mice Knockout Nonmammalian Multidisciplinary biology Gene Expression Regulation Developmental Heart Rate/genetics Myocytes Cardiac/metabolism Cell biology Embryo Action Potentials/genetics Cardiac/metabolism Knockout mouse Haploinsufficiency Cardiac Arrhythmia Cardiac function curve Calcium/metabolism Knockout Potassium/metabolism Genetically Modified Cardiac/genetics Zebrafish Proteins/genetics Animals Membrane Proteins/genetics Myocytes Ion Transport Base Sequence Organogenesis/genetics Animal Mammalian Cardiac arrhythmia Embryo Mammalian biology.organism_classification Disease Models Animal Gene Expression Regulation Genes Disease Models Mutation Genes Lethal Heart/embryology Genetic screen |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, 118(9). National Academy of Sciences Proceedings of the National Academy of Sciences of the United States of America, 118(9):e2018220118. National Academy of Sciences |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 calcium oscillations. Mechanistically, we find that Tmem161b is expressed at the cell membrane of excitable cells and live imaging shows it is required for action potential repolarization in the developing heart. Electrophysiology on isolated cardiomyocytes demonstrates that Tmem161b is essential to inhibit Ca2+ and K+ currents in cardiomyocytes. Importantly, Tmem161b haploinsufficiency leads to cardiac rhythm phenotypes, implicating it as a candidate gene in heritable cardiac arrhythmia. Overall, these data describe Tmem161b as a highly conserved regulator of cardiac rhythm that functions to modulate ion channel activity in zebrafish and mice. |
| Databáze: | OpenAIRE |
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