title: Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart.
abstract: The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (SspnKO) mice do not have heart defects, but Nkx2-5+/-/SspnKOmutants have a higher incidence of muscular VSD than Nkx2-5+/-mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5+/-/SspnKOmutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Panzer
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Suk D
authors.initials: SD
authors.lastname: Regmi
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: DePorres
authors.initials: D
authors.lastname: Cormier
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Danzo
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Iuan-Bor D
authors.initials: ID
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Julia B
authors.initials: JB
authors.lastname: Winston
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Alayna K
authors.initials: AK
authors.lastname: Hutchinson
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Salm
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Schulkey
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cochran
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.|Department of Genetics, Washington University School of Medicine, Box 8208 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006345:Heart Septal Defects, Ventricular / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000473:pathology; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D000072576:Homeobox Protein Nkx-2.5; D008565:Membrane Proteins; C095552:NKX2-5 protein, human; D009363:Neoplasm Proteins; C109646:SSPN protein, human