Rhox: A New Homeobox Gene Cluster

Homeobox genes encode transcription factors notable for their ability to regulate embryogenesis. Here, we report the discovery of a cluster of 12 related homeobox genes on the X chromosome expressed in male and female reproductive tissues in adult mice. These reproductive homeobox on the X chromosome (Rhox) genes are expressed in a cell type-specific manner; several are hormonally regulated, and their expression pattern during postnatal testis development corresponds to their chromosomal position. Most of the Rhox genes are expressed in Sertoli cells, the nurse cells in direct contact with developing male germ cells, suggesting that they regulate the expression of somatic-cell gene products critical for germ cell development. In support of this, targeted disruption of Rhox5 increased male germ cell apoptosis and reduced sperm production, sperm motility, and fertility. Identification of this family of homeobox genes provides an opportunity to study colinear gene regulation and the transcriptional control of reproduction.

[1]  K. Ahn,et al.  Psx homeobox gene is X‐linked and specifically expressed in trophoblast cells of mouse placenta , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[2]  J. Deng,et al.  Targeted Disruption of the Transition Protein 2 Gene Affects Sperm Chromatin Structure and Reduces Fertility in Mice , 2001, Molecular and Cellular Biology.

[3]  C. G. Heller,et al.  The Sertoli cell. , 2020, The Journal of clinical investigation.

[4]  K. D. Punta,et al.  Multiple new and isolated families within the mouse superfamily of V1r vomeronasal receptors , 2002, Nature Neuroscience.

[5]  M. Wilkinson,et al.  Two novel human X-linked homeobox genes, hPEPP1 and hPEPP2, selectively expressed in the testis. , 2002, Gene.

[6]  M. Matzuk,et al.  Male Reproductive Phenotypes in Double Mutant Mice Lacking Both FSHβ and Activin Receptor IIA. , 2001, Endocrinology.

[7]  M. Cantile,et al.  Homeobox genes in normal and malignant cells , 2001, Journal of cellular physiology.

[8]  P. Yen,et al.  Key apoptotic pathways for heat-induced programmed germ cell death in the testis. , 2003, Endocrinology.

[9]  Anders Gorm Pedersen,et al.  Neural Network Prediction of Translation Initiation Sites in Eukaryotes: Perspectives for EST and Genome Analysis , 1997, ISMB.

[10]  C. Vargas,et al.  Evolution of homeobox genes: Q50 Paired-like genes founded the Paired class , 1999, Development Genes and Evolution.

[11]  C. Macleod,et al.  Normal reproductive and macrophage function in Pem homeobox gene-deficient mice. , 1998, Developmental biology.

[12]  Denis Duboule,et al.  A Global Control Region Defines a Chromosomal Regulatory Landscape Containing the HoxD Cluster , 2003, Cell.

[13]  R. Krumlauf,et al.  Positive cross-regulation and enhancer sharing: two mechanisms for specifying overlapping Hox expression patterns. , 1997, Genes & development.

[14]  G. Kweon,et al.  Testosterone regulation of proto-oncogene c-myc expression in primary Sertoli cell cultures from prepubertal rats. , 1994, Journal of andrology.

[15]  R. Camerini-Otero,et al.  The mouse X chromosome is enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation , 2004, Nature Genetics.

[16]  W. Rice.  Degeneration of a nonrecombining chromosome. , 1994, Science.

[17]  Chung-I Wu,et al.  The Normal Function of a Speciation Gene, Odysseus, and Its Hybrid Sterility Effect , 2004, Science.

[18]  W. Swanson,et al.  The rapid evolution of reproductive proteins , 2002, Nature Reviews Genetics.

[19]  L. Hood,et al.  Sequence analysis of mouse vomeronasal receptor gene clusters reveals common promoter motifs and a history of recent expansion , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. Jégou.  3 The sertoli cell , 1992 .

[21]  M. Meistrich,et al.  Pem homeobox gene promoter sequences that direct transcription in a Sertoli cell-specific, stage-specific, and androgen-dependent manner in the testis in vivo. , 2003, Molecular endocrinology.

[22]  P. Holland,et al.  Evidence for 14 homeobox gene clusters in human genome ancestry , 2000, Current Biology.

[23]  L. Hurst.  Evolutionary genomics: Sex and the X , 2001, Nature.

[24]  D. Fawcett,et al.  Further observations on the numbers of spermatogonia, spermatocytes, and spermatids connected by intercellular bridges in the mammalian testis. , 1971, Biology of reproduction.

[25]  D. Duboule,et al.  Vertebrate hox gene regulation: clustering and/or colinearity? , 1998, Current opinion in genetics & development.

[26]  L. Forrester,et al.  Cloning and Characterization of Ehox, a Novel Homeobox Gene Essential for Embryonic Stem Cell Differentiation* , 2002, The Journal of Biological Chemistry.

[27]  C. P. Leblond,et al.  DEFINITION OF THE STAGES OF THE CYCLE OF THE SEMINIFEROUS EPITHELIUM IN THE RAT , 1952, Annals of the New York Academy of Sciences.

[28]  C. Amemiya,et al.  Genomics of the HOX gene cluster. , 2002, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[29]  E. Vallender,et al.  How mammalian sex chromosomes acquired their peculiar gene content. , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[30]  R. Swerdloff,et al.  Testicular heat exposure enhances the suppression of spermatogenesis by testosterone in rats: the "two-hit" approach to male contraceptive development. , 2000, Endocrinology.

[31]  M. Wilkinson,et al.  Pem Homeobox Gene Regulatory Sequences That Direct Androgen-dependent Developmentally Regulated Gene Expression in Different Subregions of the Epididymis* , 2002, The Journal of Biological Chemistry.

[32]  M. Meistrich,et al.  Effects of chemotherapy and radiotherapy on spermatogenesis. , 1993, European urology.

[33]  J. D. Engel,et al.  Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells. , 1994, Development.

[34]  B. Charlesworth.  The evolution of chromosomal sex determination. , 2002, Novartis Foundation symposium.

[35]  Yi-shiuan Tzeng,et al.  A Novel PEPP Homeobox Gene, TOX, Is Highly Glutamic Acid Rich and Specifically Expressed in Murine Testis and Ovary1 , 2004, Biology of reproduction.

[36]  M. Wilkinson,et al.  The rapidly evolving Pem homeobox gene and Agtr2, Ant2, and Lamp2 are closely linked in the proximal region of the mouse X chromosome. , 1997, Genomics.

[37]  M. Wilkinson,et al.  The Pem homeobox gene: rapid evolution of the homeodomain, X chromosomal localization, and expression in reproductive tissue. , 1996, Genomics.

[38]  M. Matzuk,et al.  Male reproductive phenotypes in double mutant mice lacking both FSHbeta and activin receptor IIA. , 2001, Endocrinology.

[39]  E. Koonin,et al.  The SPANX gene family of cancer/testis-specific antigens: rapid evolution and amplification in African great apes and hominids. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Doron Lancet,et al.  Human specific loss of olfactory receptor genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  H. Ananthaswamy,et al.  A Highly Active Homeobox Gene Promoter Regulated by Ets and Sp1 Family Members in Normal Granulosa Cells and Diverse Tumor Cell Types* , 2002, The Journal of Biological Chemistry.

[42]  Meistrich Ml.  Effects of chemotherapy and radiotherapy on spermatogenesis. , 1993 .

[43]  K. Ley,et al.  Essential Role of Neutrophils in Germ Cell-Specific Apoptosis Following Ischemia/Reperfusion Injury of the Mouse Testis1 , 2001, Biology of reproduction.

[44]  C. Geserick,et al.  OTEX, an androgen-regulated human member of the paired-like class of homeobox genes. , 2002, The Biochemical journal.

[45]  Pierre Gönczy,et al.  A single amino acid can determine the DNA binding specificity of homeodomain proteins , 1989, Cell.

[46]  K. Peterson.  Isolation of Hox and Parahox genes in the hemichordate Ptychodera flava and the evolution of deuterostome Hox genes. , 2004, Molecular phylogenetics and evolution.

[47]  Fang Yang,et al.  An abundance of X-linked genes expressed in spermatogonia , 2001, Nature Genetics.

[48]  Sudhir Kumar,et al.  MEGA2: molecular evolutionary genetics analysis software , 2001, Bioinform..

[49]  Y. Clermont.  The cycle of the seminiferous epithelium in man. , 1963, The American journal of anatomy.

[50]  M. Wilkinson,et al.  Rapid Evolution of a Homeodomain: Evidence for Positive Selection , 1997, Journal of Molecular Evolution.

[51]  R. McIsaac,et al.  Gpbox (Psx2), a homeobox gene preferentially expressed in female germ cells at the onset of sexual dimorphism in mice. , 2000, Developmental biology.

[52]  R. Reed.  After the Holy Grail Establishing a Molecular Basis for Mammalian Olfaction , 2004, Cell.

[53]  S. Carroll,et al.  Ultrabithorax regulates genes at several levels of the wing-patterning hierarchy to shape the development of the Drosophila haltere. , 1998, Genes & development.

[54]  N. M. Brooke,et al.  The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster , 1998, Nature.

[55]  D. Linzer,et al.  Rodent Prolactin Family and Pregnancy , 2001 .

[56]  G. Morata,et al.  Colinearity and functional hierarchy among genes of the homeotic complexes. , 1994, Trends in genetics : TIG.

[57]  E. Lewis.  A gene complex controlling segmentation in Drosophila , 1978, Nature.

[58]  M. Hasegawa,et al.  Radiation-induced cell death in the mouse testis: relationship to apoptosis. , 1997, Radiation research.