Independent elaboration of steroid hormone signaling pathways in metazoans

Abstract

Steroid hormones regulate many physiological processes in vertebrates, nematodes, and arthropods through binding to nuclear receptors (NR), a metazoan-specific family of ligand-activated transcription factors. The main steps controlling the diversification of this family are now well-understood. In contrast, the origin and evolution of steroid ligands remain mysterious, although this is crucial for understanding the emergence of modern endocrine systems. Using a comparative genomic approach, we analyzed complete metazoan genomes to provide a comprehensive view of the evolution of major enzymatic players implicated in steroidogenesis at the whole metazoan scale. Our analysis reveals that steroidogenesis has been independently elaborated in the 3 main bilaterian lineages, and that steroidogenic cytochrome P450 enzymes descended from those that detoxify xenobiotics.

Fig. 1.

Study background. (A) The ligand exploitation hypothesis. The ancestral receptor, that is supposed to bind estradiol, should have been lost in ecdysozoans, have lost its ligand-binding ability in mollusks, and have undergone ligand diversification through gene duplications in vertebrates. (B) The human steroid signaling pathway. (C) The steroid signaling pathways in ecdysozoans.

Fig. 2.

Simplified Maximum-likelihood phylogenies of the CYP, SDR, HSD3B, and SRD5A families in metazoans. (A) CYP family. (B) SDR family. (C) HSD3B family. (D) SRD5A family. Steroidogenic proteins are highlighted in different colors. This clearly illustrates that in most cases the steroidogenic enzymes are dispersed in the evolutionary trees, suggesting independent acquisition of their steroid specificity.

Fig. 3.

A simplified Maximum-Likelihood phylogeny of the mitochondrial clan. Vertebrate and arthropod steroidogenic enzymes are highlighted in blue and green, respectively, and the molecules they produce are indicated. These molecules are 20-OH Ecdysone for CYP314, Ecdysone for CYP315, 2deoxyecdysone for CYP302, pregnenolone for CYP11A, and cortisol for CYP11B. Colored residues in the chemical formulas are those that are modified by the catalytic reaction.

Fig. 4.

A hypothesis about the acquisition of steroidogenic pathways in metazoans. We propose that steroid sensing by NR was already present in the last common ancestor of all eumetazoans (step 1), but that steroid signaling was independently recruited many times from slightly different molecules (step 2), with subsequent refinement in some lineages (e.g., lamprey; step 3).