Cardiac gene regulatory networks in Drosophila

Abstract

The Drosophila system has proven a powerful tool to help unlock the regulatory processes that occur during specification and differentiation of the embryonic heart. In this review, we focus upon a temporal analysis of the molecular events that result in heart formation in Drosophila, with a particular emphasis upon how genomic and other cutting-edge approaches are being brought to bear upon the subject. We anticipate that systems-level approaches will contribute greatly to our comprehension of heart development and disease in the animal kingdom.

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.