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Dev Dyn
2019 May 01;2485:323-336. doi: 10.1002/dvdy.25.
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FoxN3 is necessary for the development of the interatrial septum, the ventricular trabeculae and the muscles at the head/trunk interface in the African clawed frog, Xenopus laevis (Lissamphibia: Anura: Pipidae).
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BACKGROUND: Fox genes are a large family of transcription factors that play diverse roles in the immune system, metabolism, cancer, cell cycle, and animal development. It has been shown that FoxN3 is indispensable for normal craniofacial development in the mouse and the African clawed frog, Xenopus laevis. Morpholino-mediated knockdown of FoxN3 in X. laevis delays overall development of early tadpole stages and causes eye defects, the absence of some cranial nerve branches, and malformations of the cranial skeleton and some cranial muscles, while the skeleton, nerves and muscles of the trunk are unaffected.
RESULTS: We report a delay in heart morphogenesis, the absence of the interatrial septum, and a reduction and compaction of the ventricular trabeculation after knockdown of FoxN3 in X. laevis. Furthermore, we found malformations of the cucullaris and diaphragmatico-branchialis muscles, two head muscles that develop in the head/trunk interface of X. laevis.
CONCLUSIONS: FoxN3 is necessary for the development of the interatrial septum and trabeculae in the frog heart, as well as the cranial muscles developing in the head/trunk interface. This gives the first evidence for a dependence on the head myogenic program of the cucullaris muscle in an anuran species.
Figure 1. Three‐dimensional volume reconstructions of hearts of X. laevis tadpoles based on fluorescent whole‐mount antibody stainings against desmin. A red dot in the coordinate crosses in the lower left corner indicates the position of the section plane along the dorsoventral axis. A–E: Different section levels of Co‐MO–injected control specimen at NF stage 46/47. F–J: Different section levels of bilaterally FoxN3‐MO–injected specimen at NF stage 46/47. a, atrium; aa, aortic arches; avv, atrioventricular valves; ias, interatrial septum; la, left atrium; lv, livervein; pv, pulmonary vein; ra, right atrium; ss, spiral septum; sv, sinus venosus; ta, outflow tract; v, ventricle; vt, ventricular trabeculae
Figure 2. Histological cross sections through the developing heart of Co‐MO–injected and FoxN3‐morphant X. laevis at different developmental stages. Images of Heidenhain Azan‐stained sections are converted to gray scale to enhance contrast. A–D: Uninjected control specimens. A: NF stage 40. B: NF stage 42. Blue arrows show the developing ventricular trabeculae. C: NF stage 44. Red arrows indicate the developing interatrial septum. D: NF stage 46. Red arrows indicate the interatrial septum. E–H: Bilaterally FoxN3‐MO–injected specimens. E: NF stage 40. F: NF stage 42. G: NF stage 44. H: NF stage 46. a, atrium; ias, interatrial septum; avv, atrioventricular valves; ht, heart tube; la, left atrium; ld, liver diverticle; ra, right atrium; ss, spiral septum; sv, sinus venosus; ta, outflow tract; v, ventricle; vt, ventricular trabeculae
Figure. 3. Lateral views of 3‐D surface reconstructions of μCT scans of X. laevis tadpoles at NF stage 46/47. The brain is colored in yellow, the notochord in violet, the cartilaginous head skeleton in different shades of blue, and muscles in flesh to light brown. The coordinate crosses in the lower left corner show the orientation of the hearts in relation to the body axes. A: Co‐MO–injected control specimen. A’: Close‐up of the region marked by the dashed line in A. B: Bilaterally FoxN3‐MO–injected specimen. B′: Close‐up of the region marked by the dashed line in B. BAS, branchial skeleton; cb II–IV, ceratobranchiale II–IV; cu, cucullaris muscle; db, diaphragmatico‐branchialis muscle; dl, musculus dilator larynges; etm, epaxial trunk musculature; htm, hypaxial trunk musculature; lab, levator arcum branchialium; OC, otic capsule, rc, rectus cervicis.
Figure 4. Schematic image of the interactions of FoxN3 with HDAC (A, B) and its role in cell cycle and DNA repair (C–E with FoxN3; F–H without FoxN3). Red “x!” marks indicate checkpoints for DNA damage in the G1 and G2 phases. Red lightning bolts represent DNA damage
Figure 5. Schematic illustration of the proposed interactions of cranial NCCs (blue) with cells of the FHF (red) and SHF (orange). A: Early embryo of X. laevis showing the locations of the three different cell populations. B: Cells of the FHF start to form the primary heart tube. Cells of the SHF express Fgf8, leading to increased rates of proliferation. C: Migrating NCCs inhibit Fgf8 expression in the SHF. SHF cells stop proliferation and migrate into the preformed heart tube. D: SHF cells differentiate and form the outflow tract. E: SHF cells start expression of Sema3C. Sema3C attracts NCCs and promotes migration towards the outflow tract. FHF, first heart field; NCC neural crest cell; SHF, second heart field
