The Rhox5 Homeobox Gene Regulates the Region-Specific Expression of Its Paralogs in the Rodent Epididymis1

Abstract

The mechanisms by which the region-specific expression patterns of clustered genes evolve are poorly understood. The epididymis is an ideal organ to examine this, as it is a highly segmented tissue that differs significantly in structure between closely related species. Here we examined this issue through analysis of the rapidly evolving X-linked reproductive homeobox (Rhox) gene cluster, the largest known homeobox gene cluster in metazoans. In the mouse, we found that most Rhox genes are expressed primarily in the caput region of the epididymis, a site where sperm mature and begin acquiring forward motility. This region-specific expression pattern depends, in part, on the founding member of the Rhox cluster--Rhox5--as targeted mutation of Rhox5 greatly diminishes the expression of several other family members in the caput region. In the rat, Rhox5 expression switches from the caput to the site of sperm storage: the cauda. All Rhox genes under the control of Rhox5 in the mouse epididymis display a concomitant change in their regional expression in the rat epididymis. Our results lead us to propose that widespread changes in the region-specific expression pattern of genes over evolutionary time can be the result of alterations of one or only a few master regulatory genes.

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…Besides that, transcriptional factors expressed in the epididymis control the chromatin assembly on the genome-wide level and could contribute to transmission of altered information to subsequent progeny. For example, the members of RHOX family proteins (118) and SHH (119) are essential for sperm maturation and mobility. The forkhead transcription factors, (e.g.…”

The RHOX Homeodomain Proteins Regulate the Expression of Insulin and Other Metabolic Regulators in the Testis

“…considerably in sequence between mice and rats (28,31,58), providing evidence for conservation. Consistent with their modest ability to induce Ins2 transcription, RHOX8 and RHOX11 exhibited modest binding to the Ins2 element containing the RHOX5-binding site, as demonstrated by EMSA (Fig.…”

“…To do this, we used expression vectors containing the nine other known rat Rhox genes, all of which are expressed at similar levels in transfected cells (28,37,45). We chose to generate expression vectors encoding rat Rhox genes in order to match the rat Ins2 promoter-reporter construct used for our transfection analyses.…”

“…All of the members of the Rhox gene cluster are selectively expressed in testis, epididymis, ovary, and/or placenta, suggesting that they encode a large set of transcription factors devoted to regulating and supporting fertility (19 -23). This role is likely to be conserved in other mammals, because the rat and human RHOX genes are also selectively expressed in reproductive tissues (19,(25)(26)(27)(28)(29)(30). Targeted deletion of the founding member of the Rhox cluster, Rhox5, in mice results in male subfertility, marked by increased germ cell apoptosis, reduced sperm number, and a reduced proportion of sperm with normal motility (18,19,28,31).…”

“…This role is likely to be conserved in other mammals, because the rat and human RHOX genes are also selectively expressed in reproductive tissues (19,(25)(26)(27)(28)(29)(30). Targeted deletion of the founding member of the Rhox cluster, Rhox5, in mice results in male subfertility, marked by increased germ cell apoptosis, reduced sperm number, and a reduced proportion of sperm with normal motility (18,19,28,31). Because RHOX5 is not detectably expressed in germ cells but instead is expressed in the directly adjacent Sertoli nurse cells (32)(33)(34)(35), we have previously hypothesized that the increased germ cell apoptosis in Rhox5-null mice is most likely due to the loss of one or more Sertoli cell-expressed RHOX5-dependent survival factor (31,36).…”