TY - JOUR
T1 - Silencing of the Drosophila ortholog of SOX5 in heart leads to cardiac dysfunction as detected by optical coherence tomography
AU - Li, Airong
AU - Ahsen, Osman O.
AU - Liu, Jonathan J.
AU - Du, Chuang
AU - McKee, Mary L.
AU - Yang, Yan
AU - Wasco, Wilma
AU - Newton-Cheh, Christopher H.
AU - O'Donnell, Christopher J.
AU - Fujimoto, James G.
AU - Zhou, Chao
AU - Tanzi, Rudolph E.
N1 - Funding Information:
This work was supported by the Cure Alzheimer’s Fund to R.E.T., the National Institute of Health (R01AG014713 and R01MH60009 to R.E.T.; R01CA75289 and R01HL095717 to J.G.F.; R00EB010071 to C.Z.; R03AR063271 to A.L.), the Air Force Office of Scientific Research (FA9550-07-1-0014 to J.G.F.) and a Massachusetts General Hospital ECOR Award to A.L. The Microscopy Core Facility at the MGH Program in Membrane Biology receives support from the Boston Area Diabetes and Endocrinology Research Center (DK 57521) and the Center for the Study of Inflammatory Bowel Disease (DK 43351).
PY - 2013/9
Y1 - 2013/9
N2 - The SRY-relatedHMG-box 5 (SOX5) gene encodes amember of theSOXfamily of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiacrelated endophenotypes: higher resting heart rate (HR), the electrocardiographic PR interval, atrial fibrillation and left ventricular mass. We have determined that human SOX5 has a highly conserved Drosophila ortholog, Sox102F, and have employed transgenic Drosophila models to quantitatively measure cardiac function in adult flies. For this purpose, we have developed a high-speed and ultrahigh-resolution optical coherence tomography imaging system, which enables rapid cross-sectional imaging of the heart tube over various cardiac cycles for the measurement of cardiac structural and dynamical parameters such as HR, dimensions and areas of heart chambers, cardiac wall thickness and wall velocities. We have found that the silencing of Sox102Fresulted in a significant decrease inHR, heartchambersizeandcardiac wall velocities, anda significant increase in cardiac wall thickness that was accompanied by disrupted myofibril structure in adult flies. In addition, the silencing of Sox102F in the wing led to increased L2, L3 and wing marginal veins and increased and disorganized expression of wingless, the central component of the Wnt signaling pathway. Collectively, the silencing of Sox102F resulted in severe cardiac dysfunction and structural defects with disrupted Wnt signaling transduction in flies. This implicates an important functional role for SOX5 in heart and suggests that the alterations in SOX5 levels may contribute to the pathogenesis of multiple cardiac diseases or traits.
AB - The SRY-relatedHMG-box 5 (SOX5) gene encodes amember of theSOXfamily of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiacrelated endophenotypes: higher resting heart rate (HR), the electrocardiographic PR interval, atrial fibrillation and left ventricular mass. We have determined that human SOX5 has a highly conserved Drosophila ortholog, Sox102F, and have employed transgenic Drosophila models to quantitatively measure cardiac function in adult flies. For this purpose, we have developed a high-speed and ultrahigh-resolution optical coherence tomography imaging system, which enables rapid cross-sectional imaging of the heart tube over various cardiac cycles for the measurement of cardiac structural and dynamical parameters such as HR, dimensions and areas of heart chambers, cardiac wall thickness and wall velocities. We have found that the silencing of Sox102Fresulted in a significant decrease inHR, heartchambersizeandcardiac wall velocities, anda significant increase in cardiac wall thickness that was accompanied by disrupted myofibril structure in adult flies. In addition, the silencing of Sox102F in the wing led to increased L2, L3 and wing marginal veins and increased and disorganized expression of wingless, the central component of the Wnt signaling pathway. Collectively, the silencing of Sox102F resulted in severe cardiac dysfunction and structural defects with disrupted Wnt signaling transduction in flies. This implicates an important functional role for SOX5 in heart and suggests that the alterations in SOX5 levels may contribute to the pathogenesis of multiple cardiac diseases or traits.
UR - http://www.scopus.com/inward/record.url?scp=84881539014&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt230
DO - 10.1093/hmg/ddt230
M3 - Article
C2 - 23696452
AN - SCOPUS:84881539014
SN - 0964-6906
VL - 22
SP - 3798
EP - 3806
JO - Human molecular genetics
JF - Human molecular genetics
IS - 18
M1 - ddt230
ER -