title: Silencing of the Drosophila ortholog of SOX5 in heart leads to cardiac dysfunction as detected by optical coherence tomography.
abstract: The SRY-related HMG-box 5 (SOX5) gene encodes a member of the SOX family of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiac-related 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 Sox102F resulted in a significant decrease in HR, heart chamber size and cardiac wall velocities, and a 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.
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Airong
authors.initials: A
authors.lastname: Li
authors.forename: Osman O
authors.initials: OO
authors.lastname: Ahsen
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Liu
authors.forename: Chuang
authors.initials: C
authors.lastname: Du
authors.forename: Mary L
authors.initials: ML
authors.lastname: McKee
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Wilma
authors.initials: W
authors.lastname: Wasco
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Newton-Cheh
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: James G
authors.initials: JG
authors.lastname: Fujimoto
authors.forename: Chao
authors.initials: C
authors.lastname: Zhou
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics* / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D020868:Gene Silencing; D006321:Heart / Q000502:physiology; D006801:Humans; D021621:Imaging, Three-Dimensional; D009206:Myocardium / Q000648:ultrastructure; D009210:Myofibrils / Q000502:physiology; D055747:SOX Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D055755:SOXD Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D041623:Tomography, Optical Coherence; D014921:Wings, Animal / Q000254:growth & development / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D055747:SOX Transcription Factors; C587040:SOX102F protein, Drosophila; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors; D051153:Wnt Proteins