Abstract
Congenital heart disease (CHD) is the most common birth defect, yet its genetic causes continue to be obscure. Fibroblast growth factor receptor 4 (FGFR4) recently emerged in a large patient exome sequencing study as a candidate disease gene for CHD and specifically heterotaxy. In heterotaxy, patterning of the left-right (LR) body axis is compromised, frequently leading to defects in the heart's LR architecture and severe CHD. FGF ligands like FGF8 and FGF4 have been previously implicated in LR development with roles ranging from formation of the laterality organ [LR organizer (LRO)] to the transfer of asymmetry from the embryonic midline to the lateral plate mesoderm (LPM). However, much less is known about which FGF receptors (FGFRs) play a role in laterality. Here, we show that the candidate heterotaxy gene FGFR4 is essential for proper organ situs in Xenopus and that frogs depleted of fgfr4 display inverted cardiac and gut looping. Fgfr4 knockdown causes mispatterning of the LRO even before cilia on its surface initiate symmetry-breaking fluid flow, indicating a role in the earliest stages of LR development. Specifically, fgfr4 acts during gastrulation to pattern the paraxial mesoderm, which gives rise to the lateral pre-somitic portion of the LRO. Upon fgfr4 knockdown, the paraxial mesoderm is mispatterned in the gastrula and LRO, and crucial genes for symmetry breakage, like coco, xnr1, and gdf3 are subsequently absent from the lateral portions of the organizer. In summary, our data indicate that FGF signaling in mesodermal LRO progenitors defines cell fates essential for subsequent LR patterning.
Highlights
Left-right (LR) asymmetry is a major characteristic of the vertebrate body plan
F0 CRISPR for all three Small guide RNAs (sgRNAs) led to tadpoles with cardiac L-loops and inverted gut looping (Figures 1A–C), indicating that fgfr4 plays a role in establishing organ laterality
We propose a role for the candidate heterotaxy gene Fibroblast growth factor receptor 4 (FGFR4) in pattering the paraxial mesoderm, which contributes to the formation of the lateral LR organizer (LRO)
Summary
Left-right (LR) asymmetry is a major characteristic of the vertebrate body plan. While externally symmetric, chordates display a specific internal LR arrangement of their visceral organs. LR development is defective and organs are mispatterned relative to the LR axis, which often results in compromised LR architecture of the heart and clinically severe cardiac dysfunction. Heterotaxy is a predominantly genetic disease, causal genes remain largely unidentified (Zaidi and Brueckner, 2017). Exome sequencing of congenital heart disease (CHD) patients identified three individuals with damaging mutations in fibroblast growth factor receptor 4 (FGFR4). The first patient, with hypoplastic left heart syndrome, had a de novo mutation (Asp297Asn). The second patient, with an L-transposition of the great arteries and tricuspid atresia, had an inherited stopgain at Gly705. A third patient had an inherited damaging splice mutation associated with a hypoplastic main pulmonary artery and a left superior vena cava that
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