Distinct myocardial lineages break atrial symmetry during cardiogenesis in zebrafish

Abstract

The ultimate formation of a four-chambered heart allowing the separation of the pulmonary and systemic circuits was key for the evolutionary success of tetrapods. Complex processes of cell diversification and tissue morphogenesis allow the left and right cardiac compartments to become distinct but remain poorly understood. Here, we describe an unexpected laterality in the single zebrafish atrium analogous to that of the two atria in amniotes, including mammals. This laterality appears to derive from an embryonic antero-posterior asymmetry revealed by the expression of the transcription factor gene meis2b. In adult zebrafish hearts, meis2b expression is restricted to the left side of the atrium where it controls the expression of pitx2c, a regulator of left atrial identity in mammals. Altogether, our studies suggest that the multi-chambered atrium in amniotes arose from a molecular blueprint present before the evolutionary emergence of cardiac septation and provide insights into the establishment of atrial asymmetry.

Asymmetric Hapln1a drives regionalised cardiac ECM expansion and promotes heart morphogenesis during zebrafish development

“…At 26hpf hapln1a expression is upregulated on the 176 left side of the cardiac tube with elevated levels of expression of hapln1a in the future atrium 177 compared to the future ventricle, recapitulating the regionalised ECM expansion we observe 178 in the heart (compare Fig 2E and Fig 1K). This is in line with recent studies demonstrating that 179 the posterior compartment of the cardiac disc is re-positioned to the left side of the heart tube 180 (Guerra et al 2018). By 50hpf hapln1a expression is restricted to very low levels in the 181 atrioventricular canal, the precursor to the atrioventricular valve ( Fig 2F).…”

“…Analysis 343 of meis2b mutants revealed defects in atrial morphology at juvenile and adult stages, supporting 344 our conclusion that early anterior-posterior asymmetry in the heart disc/left-right asymmetry 345 in the heart tube are important for continual cardiac morphogenesis. However, contrary to our 346 study which reveals a reduced atrial size in hapln1a mutants, meis2b mutant adult zebrafish 347 exhibit an enlarged atrium (Guerra et al 2018) suggesting that while they are expressed in the same domain, these two genes regulate atrial morphogenesis differently. hapln1a mutants are 349 adult viable (data not shown), therefore it would be interesting to determine whether the atrium 350 remains underdeveloped in hapln1a mutants, or whether they also develop a hyperproliferative 351 atrial hypertrophy phenotype by adulthood.…”

“…Together, we propose a model where initiation of hapln1a expression in the posterior cardiac 319 disc is independent of KV-based laterality cues, but the subsequent cell movements which 320 occur during heart tube formation reposition this population of cells to the left side of the heart, 321 dictating the axis of ECM asymmetry in the heart tube (Guerra et al 2018). Therefore, 322 embryonic laterality positions the regionally specialized ECM in the heart tube, ensuring that 323 directionality and growth of the heart are tightly coordinated to fine tune cardiac 324 morphogenesis.…”

“…340 hapln1a mutants exhibit mild defects in cardiac morphology at embryonic stages, with atrial 341 morphology predominantly affected. Interestingly, the only other gene shown to be expressed 342 in the posterior cardiac disc/left heart tube in zebrafish is meis2b (Guerra et al 2018). Analysis 343 of meis2b mutants revealed defects in atrial morphology at juvenile and adult stages, supporting 344 our conclusion that early anterior-posterior asymmetry in the heart disc/left-right asymmetry 345 in the heart tube are important for continual cardiac morphogenesis.…”

Cardiac septation in heart development and evolution

“…These facts indicate that the Tbx5 ‐Hh network is important for atrial septum formation though Tbx5‐downstream targets, such as Gas1 , Osr1 , and Cdk6 (Xie et al., ; Figure b,c). Furthermore, a recent study demonstrated that in zebrafish, the species with no cardiac septum, transcription factor meis2b shows an expression pattern restricted to the left side of the atrium, and this expression pattern is important for establishment of atrial asymmetry through regulation of pitx2c expression (Guerra et al., ). These facts indicate that the molecular blueprint exists even under the situation without cardiac septation, and the genes that show restricted expression are important for establishment of atrial asymmetry and septation.…”