Evolution of gene regulatory networks controlling body plan development

Abstract

Evolutionary change in animal morphology results from alteration of the functional organization of the gene regulatory networks (GRNs) that control development of the body plan. A major mechanism of evolutionary change in GRN structure is alteration of cis-regulatory modules that determine regulatory gene expression. Here we consider the causes and consequences of GRN evolution. Although some GRN subcircuits are of great antiquity, other aspects are highly flexible and thus in any given genome more recent. This mosaic view of the evolution of GRN structure explains major aspects of evolutionary process, such as hierarchical phylogeny and discontinuities of paleontological change.

Fig. 1. Cis-regulatory mutations resulting in co-optive change in domain of expression of a regulatory gene, and examples of possible consequences at the GRN level

(A) Co-option event: The gene regulatory networks operating in spatial Domains 1 and 2 produce different regulatory states (colored balls, representing diverse transcription factors). A cis-regulatory module of Gene A, a regulatory gene, has target sites for factors present in the Domain 1 regulatory state and so Gene A and its downstream targets are expressed in Domain 1, but not in Domain 2 where only one of the three sites can be occupied. Two alternative types of cis-regulatory mutations are portrayed: appearance of new sites within the module by internal nucleotide sequence change; and transposition into the DNA near the gene of a module from elsewhere in the genome bearing new sites. While these gain of function changes do not affect the occupancy of the cis-regulatory sites of Gene A in Domain 1, the new sites allow Gene A to respond to the regulatory state of Domain 2, resulting in a co-optive change in expression so that Gene A is now active in Domain 2 (modified from Davidson and Erwin, 2010). (B) Gain of function changes in Domain 2 GRN architecture caused by co-option of Gene A: Gene A might control expression of an inductive signaling ligand, which could alter the fate/function of adjacent cells now receiving the signal from Domain 2 (left); Gene A might control expression of Gene B, another regulatory gene, and together with it cause expression of a differentiation (D) gene battery, which in consequence of the cooption is now expressed in Domain 2 (right).

Fig. 2. Functional evolutionary consequences of cis-regulatory mutations depend on their location in GRN architecture

A GRN circuit encoding the control system of a differentiation gene battery (bottom tiers) activated in response to a signal (S) from adjacent cells (top tier); linkages shown in gray and genes in black. The double arrow indicates signal reception and transduction causing gene expression in the recipient cells. Note that the middle tier of circuitry consists of a dynamic feedback stabilization subcircuit. The numbered red “x” symbols denote mutational changes in the cis-regulatory modules controlling expression of these genes, keyed by number to the functional consequences listed in the box below. Loss of function mutations (1 and 2) are indicated in green, and co-optive gain of function mutations (3 and 4) resulting in expression of the affected gene in a new domain, as in Fig.1A, are indicated in gray (modified from Erwin and Davidson, 2009).

Fig. 3. Symbolic representation of hierarchy in developmental GRNs

The developmental process begins with the onset of embryogenesis at top. The outputs of the initial (i.e., pregastrular) embryonic GRNs (“Embryonic pattern formation GRN”) are used after gastrulation to set up the GRNs which establish regulatory states throughout the embryo, organized spatially with respect to the embryonic axes (axial organization and spatial subdivision are symbolized by orthogonal arrows and colored patterns). These spatial domains divide the embryonic space into broad domains occupied by pluripotential cell populations already specified as mesoderm, endoderm, future brain, future axial neuroectoderm, non-neural ectoderm, etc. The GRNs establishing this initial mosaic of postgastrular regulatory states, including the signaling interactions that help to establish domain boundaries, are symbolized as Box I. Within Box I domains the progenitor fields for the future adult body parts are later demarcated by signals plus local regulatory spatial information formulated in Box I, and given regulatory states are established in each such field by the earliest body part specific GRNs. Many such progenitor fields are thus set up during postgastrular embryogenesis, and a GRN defining one of these is here symbolized as Box II. Each progenitor field is then divided up into the subparts that will together constitute the body part, where the subdivisions are initially defined by installation of unique GRNs producing unique regulatory states. These “sub-body part” GRNs are symbolized by the oriented patterns of Box III. Since some body parts are ultimately of great complexity, the process of patterned subdivision and installation of successively more confined GRNs may be iterated, like a “do-loop”, symbolized here by the upwards arrow from Box III to Box II, labeled n≥1. Towards the termination of the developmental process in each region of the late embryo, the GRNs specifying the several individual cell types and deployed in each subpart of each body part, are symbolized here as Box IV. Post-embryonic generation of specific cell types (from stem cells) is a Box IV process as well. At the bottom of the diagram are indicated several differentiation gene batteries (“DGB1,2,3”), the final outputs of each cell type. Morphogenetic functions are also programmed in each cell type (not shown). For discussion and background see text and Davidson, 2001; .