Uncovering the molecular and cellular mechanisms of heart development using the zebrafish

Abstract

Over the past 20 years, the zebrafish has emerged as a powerful model organism for studying cardiac development. Its ability to survive without an active circulation and amenability to forward genetics has led to the identification of numerous mutants whose study has helped elucidate new mechanisms in cardiac development. Furthermore, its transparent, externally developing embryos have allowed detailed cellular analyses of heart development. In this review, we discuss the molecular and cellular processes involved in zebrafish heart development from progenitor specification to development of the valve and the conduction system. We focus on imaging studies that have uncovered the cellular bases of heart development and on zebrafish mutants with cardiac abnormalities whose study has revealed novel molecular pathways in cardiac cell specification and tissue morphogenesis.

Figure 1

Overview of zebrafish heart development. (a–c) Heart development before looping. Embryos are shown in a dorsal view. (a) At 12 hours post-fertilization (hpf) (15 somites), myocardial progenitors are found in the anterior lateral plate mesoderm (ALPM), with ventricular progenitors more medial than atrial progenitors. Endocardial progenitors lie anterior in the ALPM. (b) Myocardial and endocardial progenitors migrate to the midline and fuse by 19 hpf (20 somites) to create the cardiac cone. (c) Through a process of involution, the myocardium rearranges to surround the endocardium and form the linear heart tube by 24 hpf. (d–e) Later heart development. Heart sections are shown from a ventral view. (d ) By 48 hpf, the heart has looped to form a right-sided ventricle and left-sided atrium. Distinct outer and inner curvatures can be distinguished, and the outer curvature (OC) of the ventricle has started to balloon. The atrioventricular (AV) myocardium has functionally differentiated to introduce a conduction delay, and pacemaker activity has become restricted to the sinoatrial (SA) ring. The proepicardial organ has coalesced near the AV canal. (e) By 120 hpf, the OC of the ventricle has more fully ballooned, and trabecular ridges have started to appear. The AV valve leaflets are well formed and prevent retrograde flow. The epicardium has expanded over the entire exterior surface of the myocardium. The SA nodal tissue is most often restricted to a few cells on the right side of the atrium several cell diameters away from the SA ring.

Figure 2

Zebrafish valve development. (a) By 55 hpf, the atrioventricular (AV) endocardium forms a thick monolayer. (b) By 60 hpf, the endocardial layer shows signs of involution. (c) By 72 hpf, a superior leaflet has formed through the involution of a few distinct AV endocardial cells. (d ) By 96 hpf, both superior and inferior leaflets have formed. (e) Retrograde flow of blood cells observed over developmental time. By 72 hpf, retrograde flow has essentially ceased. Modified from 107.