title: Retinoid signaling is required to complete the vertebrate cardiac left/right asymmetry pathway.
abstract: Vitamin A-deficient (VAD) quail embryos have severe abnormalities, including a high incidence of reversed cardiac situs. Using this model we examined in vivo the physiological function of vitamin A in the left/right (L/R) cardiac asymmetry pathway. Molecular analysis reveals the expression of early asymmetry genes activin receptor IIa, sonic hedgehog, Caronte, Lefty-1, and Fgf8 to be unaffected by the lack of retinoids, while expression of the downstream genes nodal-related, snail-related (cSnR), and Pitx2 is altered. In VAD embryos nodal expression in left lateral plate mesoderm (LPM) is severely downregulated and the expression domain altered during neurulation. Similarly, the expression of cSnR in the right LPM and of Pitx2 in the left side posterior heart-forming region (HFR) is downregulated in the VAD embryos. The lack of retinoids does not cause randomization or ectopic expression of nodal, cSnR, or Pitx2. At the six- to eight-somite stage nodal is expressed transiently in the left posterior HFR of normal quail embryos; this expression is missing in VAD embryos and may be linked to the loss of Pitx2 expression in this region of VAD quail embryos. Administration of retinoids to VAD embryos prior to the six-somite stage rescues the expression of nodal, cSnR, and Pitx2 as well as the randomized VAD cardiac phenotype. There is an absolute requirement for retinoids at the four- to five-somite developmental window for cardiogenesis and cardiac L/R specification to proceed normally. We conclude that retinoids do not regulate the left/right-specific sidedness assignments for expression of genes on the vertebrate cardiac asymmetry pathway, but are required during neurulation for the maintenance of adequate levels of their expression and for the development of the posterior heart tube and a loopable heart. Cardiac asymmetry may be but one of several critical events regulated by retinoid signaling in the retinoid-sensitive developmental window.
authors.affiliation: Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, 48824, USA. zile@msu.edu
authors.forename: M H
authors.initials: MH
authors.lastname: Zile
authors.forename: I
authors.initials: I
authors.lastname: Kostetskii
authors.forename: S
authors.initials: S
authors.lastname: Yuan
authors.forename: E
authors.initials: E
authors.lastname: Kostetskaia
authors.forename: T R
authors.initials: TR
authors.lastname: St Amand
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Jiang
mesh_terms: D030301:Activin Receptors, Type II; D000818:Animals; D030161:Avian Proteins; D019521:Body Patterning; D004268:DNA-Binding Proteins / Q000302:isolation & purification; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000302:isolation & purification; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000209:etiology; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000302:isolation & purification; D055458:Left-Right Determination Factors; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D011506:Proteins / Q000302:isolation & purification; D011784:Quail; D017978:Receptors, Growth Factor / Q000302:isolation & purification; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction; D019170:Somites; D014018:Tissue Distribution; D015534:Trans-Activators; D014157:Transcription Factors / Q000302:isolation & purification; D016212:Transforming Growth Factor beta / Q000302:isolation & purification; D014801:Vitamin A / Q000378:metabolism*; D014802:Vitamin A Deficiency; D000097577:Homeobox Protein PITX2
chemical_list: D030301:Activin Receptors, Type II; D030161:Avian Proteins; D004268:DNA-Binding Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D055458:Left-Right Determination Factors; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D011506:Proteins; D017978:Receptors, Growth Factor; D012176:Retinoids; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014801:Vitamin A; D000097577:Homeobox Protein PITX2; C526161:LEFTY1 protein, human; C121419:caronte protein, Gallus gallus; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3