Sept7bis required for the subcellular organization of cardiomyocytes and cardiac function in zebrafish.
Myofibrils made up of actin, myosin, and associated proteins generate the contractile force in muscle, and, consequently, mutations in these proteins may lead to heart failure. Septins are a conserved family of small GTPases that associate with actin filaments, microtubules, and cellular membranes. Despite the importance of septins in cytoskeleton organization, their role in cardiomyocyte organization and function is poorly characterized. Here, we show that septin 7 is expressed in both embryonic and adult zebrafish hearts and elucidate the physiological significance ofsept7b, the zebrafish ortholog of human septin 7, in the heart in embryonic and larval zebrafish. Knockdown ofsept7breduced F-actin and α-cardiac actin expression in the heart and caused disorganization of actin filaments. Electron microscopy ofsept7b-depleted larvae showed disorganization of heart myofibrils and partial detachment from Z-disks. Functional studies revealed that knockdown ofsept7bleads to reduced ventricular dimensions, contractility, and cardiac output. Furthermore, we found that depletion ofsept7bdiminished the expression of retinaldehyde dehydrogenase 2, which catalyzes the synthesis of retinoic acid necessary for heart morphogenesis. We further observed that thesept7band retinoic acid signaling pathways converge to regulate cardiac function. Together, these results specify an essential role forsept7bin the contractile function of the heart.NEW & NOTEWORTHYKnockdown of the zebrafish ortholog of human septin 7 (sept7b) destabilizes cardiac actin and reduces ventricular dimensions, contractility, and cardiac output in larval zebrafish, indicating thatsept7bis essential for cardiac function. We further found thatsept7band retinoic acid signaling pathways converge to regulate cardiac function. These data prompt further studies defining the role ofsept7bin cardiomyopathies.
Department of Pathology, University of Helsinki, Helsinki, Finland.
Surjya Narayan
SN
Dash
Unit of Cardiovascular Research, Minerva Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland.
Suneeta
S
Narumanchi
Unit of Cardiovascular Research, Minerva Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland.|Internal Medicine, Jorvi Hospital, Helsinki University Hospital, Espoo, Finland.
Jere
J
Paavola
Unit of Cardiovascular Research, Minerva Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland.
Sanni
S
Perttunen
Department of Pathology, University of Helsinki, Helsinki, Finland.
Hong
H
Wang
Unit of Cardiovascular Research, Minerva Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland.|Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; and.
Päivi
P
Lakkisto
Unit of Cardiovascular Research, Minerva Institute for Medical Research, Biomedicum Helsinki, Helsinki, Finland.|Abdominal Center, Nephrology, Helsinki University Hospital, Helsinki, Finland.
Ilkka
I
Tikkanen
Department of Pathology, University of Helsinki, Helsinki, Finland; sanna.h.lehtonen@helsinki.fi.
Sanna
http://orcid.org/0000-0003-4189-2415
S
Lehtonen
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D009024:Morphogenesis / Q000502:physiology*; D032342:Muscle Cells / Q000502:physiology*; D058112:Septins / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism*; D016276:Ventricular Function / Q000502:physiology*; D015027:Zebrafish / Q000502:physiology*; D029961:Zebrafish Proteins / Q000378:metabolism*
C000621982:Sept7b protein, zebrafish; D029961:Zebrafish Proteins; D058112:Septins
actin; differentiation; myofibril; retinaldehyde dehydrogenase 2; retinoic acid; septin 7