Gene regulatory networks in the evolution and development of the heart

Abstract

The heart, an ancient organ and the first to form and function during embryogenesis, evolved by the addition of new structures and functions to a primitive pump. Heart development is controlled by an evolutionarily conserved network of transcription factors that connect signaling pathways with genes for muscle growth, patterning, and contractility. During evolution, this ancestral gene network was expanded through gene duplication and co-option of additional networks. Mutations in components of the cardiac gene network cause congenital heart disease, the most common human birth defect. The consequences of such mutations reveal the logic of organogenesis and the evolutionary origins of morphological complexity.

Fig. 1

Evolution of the heart and the core cardiac transcription factors. The structures of the hearts of representative animals and their evolutionary relationships are shown. The numbers of cardiac regulatory genes, which are known to be expressed in the cardiac structures of each organism, are shown.

Fig. 2

Simplified structures of different types of hearts, showing schematic diagrams of hearts and directions of blood flow. (A) Simple chordates have tubular hearts, some of which pump bidirectionally. The hearts of ancestral bilaterians probably had a similar structure. Fish hearts (B) have a single atrium and ventricle, whereas the hearts of reptiles, birds, and mammals (C) have two atrial and two ventricular chambers. Oxygenated blood is shown in red and deoxygenated blood in blue.

Fig. 3

The heart of Drosophila. (A) The heart of a Drosophila embryo visualized by the expression of green fluorescent protein under control of the cardiac enhancer of the Hand gene. Hemolymph enters the heart at the posterior end of the embryo through ostia and is pumped anteriorly. (B) A simplified diagram of the core transcriptional network of Drosophila heart development.

Fig. 4

Schematic of transcriptional networks involved in mammalian heart development. (A) Inductive signals activate a set of upstream regulatory genes, encoding transcription factors, in the primary and secondary heart fields. The products of these genes activate the genes in the core cardiac network (NK2-MEF2-GATA-Tbx-Hand). Some components of the network, such as Nkx2-5, are also activated in the primary heart field in response to inductive signals. The core network genes cross- and autoregulate their expression and serve as the central regulatory network for the activation of muscle-specific genes and genes that control the growth and patterning of derivatives of the primary and secondary heart fields. The primary heart field gives rise to the left ventricle (lv) and portions of the atria (a), whereas the secondary heart field gives rise to the right ventricle (rv), portions of the atria, and the outflow tract. A scanning electron micrograph of a mouse heart at embryonic day 14.5 is shown at the bottom. Derivatives of primary and secondary heart fields are shown in blue and pink, respectively. The atria, which are derived from the primary and secondary heart fields, are shown in purple. (B) Regulatory interactions among cardiac transcription factors in the secondary heart field. Solid lines indicate direct transcriptional connections, and dotted lines indicate connections not yet shown to be direct. [Adapted from (9)]