Rhox5 Rules in an Evolving Saga of Reproductive Diversity

Homeobox (Hox) genes encode several subfamilies of nuclear proteins with structurally conserved helix-turn-helix domains that recognize specific DNA sequences [1]. As transcription factors, HOX family members control key events during early development, influencing the organization of body patterning and tissue structures in all species of the animal kingdom from invertebrates to humans [1, 2]. In fully developed organisms, Hox genes contribute to tissue damage and repair mechanisms by controlling apoptosis, receptor signaling, differentiation, motility, and angiogenesis; when expressed abnormally, these activities can have oncogenic consequences [3]. Rhox5 was first identified by Wilkinson et al. [4] as an oncofetal gene (originally called Pem because it was expressed in placenta and embryos) that influenced the progression of Tcell lymphomas to their oncogenic phenotype. During the decade following its discovery, Pem was classified as an orphan member of the Hox gene family that is selectively expressed in reproductive tissues. It therefore followed that Pem was renamed Rhox5 when it was located within a syntenically conserved cluster of other, related reproductive Hox genes on the mouse X chromosome, which was dubbed the Rhox gene family locus in a groundbreaking report in 2005 [5]. In the intervening years, MacLean, Wilkinson, and their colleagues defined the roles of Rhox genes in reproductive tissues [6]. In an elegant report published in the current issue of Biology of Reproduction, MacLean et al. [7] have integrated the power of mouse genetics with the emerging discipline of comparative genomics to gain insight into how Rhox gene expression is regulated within specific regions of the epididymis. The rodent epididymis is ideal for these studies because of its well-established segmentation into three anatomically and functionally distinct regions; the head, or caput; the main body, or corpus; and the tail, or cauda. Over the ;16M years since the Mus/Rattus evolutionary divergence, the segmented anatomical arrangement of the rodent epididymis has remained intact, but each of the segments has acquired distinct roles in terms of the maturation and storage of spermatozoa in the different species. In a clear example of this, the caput epididymidis of mice plays a key role in sperm maturation and the acquisition of forward motility, whereas this occurs in the rat cauda epididymidis, which is normally considered to be a site of sperm storage. Building on a previous finding that the sperm of Rhox5 null mice lack forward motility [5], MacLean et al. [7] embarked on a series of experiments. Their results now show that Rhox5 is a master regulator of many other members of the X-linked Rhox gene cluster in the mouse caput epididymidis and that it acts in almost the same way in the rat cauda epididymidis. This remarkable evolutionary shift in the Rhox5-dominated regionspecific expression of Rhox genes in the rodent epididymis sets the stage for additional experiments that promise to provide insight into mechanisms responsible for the functional maturation of sperm. Comparative studies of gene expression profiles of different segments of the rat and mouse epididymis have already been performed [8], and similar studies will undoubtedly follow in mice with either a functional or a disrupted Rhox5 gene. This should help define whether Rhox5 or other members of the Rhox family act directly or indirectly by controlling spatially defined networks of genes to explain why sperm from the mouse caput and corpus epididymidis are functionally much more mature than rat sperm taken from the same anatomical locations. These types of studies integrate the power of comparative genomics with a wealth of information about the functional diversity of reproductive tissues in two closely related species, and they offer huge potential for the discovery of key mechanisms that control male fertility. In this context, the report by MacLean et al. [7] is a harbinger of many other such studies that will follow in the wake of the Genome10K Project (http://www.genome10k.org), which sets out to assemble the genomic DNA sequences of 10 000 vertebrate species and to thereby cover every vertebrate genus. When overlaid on the well-documented diversity in reproductive strategies within the animal kingdom and the remarkable evolutionary divergence of reproductive anatomy and physiology that occurs in even the most closely related of species, these genomic data sets are in essence the virtual keys that may allow us to unlock many of the secrets that have long eluded reproductive biologists. This new age of comparative genomics is fast approaching, and it will have a huge impact on fields like reproductive biology, where sometimes dramatic biological adaptations have occurred in concert with rapid evolutionarily changes in the sequences of genes, like the Rhox family. It can be anticipated that these rapidly evolving genes will surface as the drivers or mediators of adaptive mechanisms that have ensured the diversity and, ultimately, the survival of species. Most important, these advances in knowledge are poised to occur quickly and can be expected to reveal new and unexpected ways of modifying the fertility of different species across the animal kingdom.

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