Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewCardiac gene regulatory networks in Drosophila
Introduction
A central goal of developmental biology is to identify and characterize the genes which control the formation of specific cells, tissues, or organs within the body. Much recent progress has been driven by the increasing realization that genes controlling organ formation are implicated in congenital birth defects, as well as diseases in later life. Thus, genes whose normal function is to create cell types in the embryo, can also destroy those structures when mutated. Of equal importance, it is now apparent that genes showing evolutionary conservation in sequence frequently show evolutionary conservation in function. Thus, the analysis of development in model organisms has provided important insight into developmental mechanisms (reviewed in [1]).
It is also apparent that the complex tissues and organs of higher animals arise from the concerted actions of very large numbers of genes influencing cell behavior and function. These genes, many of them regulatory in nature, are known to function as components of regulatory networks; and there is increasing evidence that the genetic networks have also been conserved through evolution. Defining the parameters of such regulatory networks, and how the networks have evolved, has become a central challenge in the field (reviewed in [2]).
One of the earliest organs to form in the mammalian body is the heart. Significant progress has been made in defining the genes which contribute to heart development, in a diverse array of animal models (reviewed in [3], [4], [5]). Many of these critical genes play regulatory roles, and the roles of individual genes in contributing to the overall genomic regulatory network for cardiogenesis is becoming clear.
We recently presented a developmental regulatory network for cardiogenesis in Drosophila and mammals, drawing attention to the striking conservation in function for several named factors [3]. While this network provides insight into the cadre of genes controlling cardiac development, it does not provide a sense for how regulatory interactions change over time. In addition, it does not take into account the plethora of new information and new technologies available to the developmental cardiologist. As more data become available, it is incumbent upon us to find ways to analyze the data and to use it to generate predictive models regarding both normal cardiac development and cardiac disease mechanisms.
In this review, we have updated the gene regulatory interactions that are known to take place during Drosophila cardiac development. In doing this, we have parsed the embryonic period to a series of critical stages, and we have focused upon the known regulatory events taking place at each stage. This allows us to visualize cardiac development as a series of interdependent processes, starting prior to gastrulation, and culminating in the formation of a functioning heart tube only 20 hours later.
Section snippets
The embryology of Drosophila cardiac development
Cardiac tissue in Drosophila, as in other animals, arises from the mesoderm. The cellular details of cardiac cell specification and morphogenesis are described in Fig. 1. Mesodermal cells are specified early in fly development as a ventral group of cells, which invaginates to form a layer within the embryo (Fig. 1A–A”). Mesodermal cells then spread laterally and dorsally, and those that migrate the furthest become restricted to a dorsal mesoderm fate via the action of the dorsally-derived TGFß
The dorsoventral axis: several domains contribute to cardiac specification
The first critical decision made during the formation of cardiac tissue is to pattern the embryo along the dorsoventral axis. The dorsoventral patterning mechanism promotes the formation of a gradient of nuclear Dorsal protein from low in the dorsal region, through moderate in lateral regions, to high in ventral regions (Fig. 2). On a superficial level, this decision is important since it results in the specification of the mesoderm as the ventral-most group of cells in response to the highest
The dorsal mesoderm
Specification of the dorsal mesoderm begins when the underlying mesodermal layer comes into the vicinity of the dorsal ectoderm (Fig. 1B–B”). In response to the ectodermally produced Dpp signal, the dorsal ridge of the mesodermal layer is specified, as expression of a number of molecular markers becomes restricted to this region. Specifically, expression of the cardiogenic factor tinman (tin) narrows down from the broad expression in trunk mesoderm to a slimmer band corresponding to the dorsal
Specification of distinct progenitors within the cardiac mesoderm: the Eve pericardial cell
By the end of stage 10 of Drosophila embryogenesis, the newly formed cardiac mesoderm comprises spaced clusters of cells situated at the dorsal ridge of the mesoderm, under the intersection points between Dpp and Wg ectodermal signals [38]. From this presumptive cardiac field, three elements emerge: a subset of dorsal body wall muscles; cardial cells (cardiomyocytes); and pericardial cells. There is still much to learn about the mechanisms that specify cardial cell progenitors at this stage. By
Diversifying the cardiac tube: the anteroposterior axis
As the linear cardiac tube is being formed via the convergence of two rows of cardial cells, cells along the anteroposterior (AP) axis are programmed to assume distinct cell fates. This programming is most apparent in the patterning of Svp cells in the developing dorsal vessel: whereas ten trunk segments contribute cells to the cardiac tube, only in the most posterior seven segments do Svp cells form. There are additionally a number of genes, both regulatory and structural, whose patterns of
Cardiac structural genes: a common code for a common pattern of expression?
Expression of a set of genes that directly determine cardiac function is the ultimate goal of the differentiation process, yet as described below, significant diversity is apparent both in patterns of structural gene expression and mechanisms of structural gene regulation. Cardiac structural genes can be tentatively grouped into sub-categories of (i) general muscle-specific genes and (ii) cardiac-specific genes, although there are also several genes, such as svp and brokenhearted, which show
Concluding comments
Significant progress has been made over the last few years in identifying how cardiac cells are specified in the embryo and how their differentiation is regulated. It is now apparent that the process of cardiogenesis, in organisms from flies to man, arises from the action of a conserved network of regulatory interactions. New technological approaches are further identifying genes which are expressed in the cardiac tissue, defining their functions in that tissue, and demonstrating how their
Acknowledgements
Research in the Cripps Laboratory is supported by grants from the NIH (GM61738, HL080545) American Heart Association, Pacific-Mountain Affiliate, and the March of Dimes Birth Defects Foundation.
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