The homeotic genes, whose products serve as determinants of embryonic cell fate, are expressed in a series of different
but partially overlapping domains that extend along the anterior-posterior (A-P) axis of the embryo. The Hox genes
share a 180-bp homeo box, which encodes a 60-amino acid homeodomain that binds specifically to DNA. There are 4
Hox gene clusters: HOXA (formerly HOX1) on chromosome 7, HOXB (formerly HOX2) on chromosome 17, HOXC
(formerly HOX3) on chromosome 12, and HOXD (formerly HOX4) on chromosome 2. By sequence comparison, the
genes of each cluster are assigned to 1 of 13 groups. The order of the HOX genes along the chromosome reflects where
they are expressed along the body axis.
NCBI Summary:
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. This gene is highly similar to the antennapedia (Antp) gene of Drosophila.
General function
Cell proliferation, Nucleic acid binding, DNA binding, Transcription factor
Comment
cDNA cloning and expression of the human NOBOX gene in oocytes and ovarian follicles. Huntriss J et al. Nobox is a homeobox gene that is preferentially expressed in the oocytes and is essential for folliculogenesis and the regulation of oocyte-specific gene expression in the mouse. The likely human homologue has been identified in silico but has not as yet been confirmed experimentally. Here, we present the first cDNA cloning and transcript expression analysis of the human NOBOX gene. Using RT-PCR, we reveal that expression within adult human tissues is limited to the ovary, testis and pancreas. Expression within the ovary is oocyte specific, with expression observed from the primordial stage ovarian follicle through to the metaphase II (MII) oocyte. In complementary studies, we reveal dynamic expression profiles of 14 additional homeobox genes throughout human oogenesis and early development. The expression of HOXA10 is restricted to primordial and early primary follicles. HOXB7 is expressed from primordial and early primary stage follicles through to germinal vesicle (GV) oocytes. Gastrulation brain homeobox 1 (GBX1) and HOXA7 genes are homeobox markers preferentially expressed by GV oocytes. HOXA1 and HEX are homeobox markers preferentially expressed by MII oocytes. In summary, the homeobox gene transcripts that are detected in ovarian follicles and oocytes are distinct from those expressed in human blastocysts (HOXB4, CDX2 and HOXC9) and granulosa cells (HOXC9, HOXC8, HOXC6, HOXA7, HOXA5 and HOXA4).
Cellular localization
Nuclear
Comment
Ovarian function
ovarian tumor
Comment
Naora H, et al 2001 reported the aberrant expression of homeobox gene HOXA7 is associated with mullerian-like differentiation of epithelial ovarian tumors
and the generation of a specific autologous antibody response.
Expression regulated by
Growth Factors/ cytokines, GDF9
Comment
Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells. Zhang Y et al. ABSTRACT: BACKGROUND: Homeobox (HOX) genes encode transcription factors, which regulate cell proliferation, differentiation, adhesion, and migration. The deregulation of HOX genes is frequently associated with human reproductive system disorders. However, knowledge regarding the role of HOX genes in human granulosa cells is limited. METHODS: To determine the role of HOXA7 in the regulation and associated mechanisms of cell proliferation in human granulosa cells, HOXA7 and epidermal growth factor receptor (EGFR) expressions were examined in primary granulosa cells (hGCs), an immortalized human granulosa cell line, SVOG, and a granulosa tumor cell line, KGN, by real-time PCR and Western blotting. To manipulate the expression of HOXA7, the HOXA7 specific siRNA was used to knockdown HOXA7 in KGN. Conversely, HOXA7 was overexpressed in SVOG by transfection with the pcDNA3.1-HOAX7 vector. Cell proliferation was measured by the MTT assay. RESULTS: Our results show that HOXA7 and EGFR were overexpressed in KGN cells compared to hGCs and SVOG cells. Knockdown of HOXA7 in KGN cells significantly decreased cell proliferation and EGFR expression. Overexpression of HOXA7 in SVOG cells significantly promoted cell growth and EGFR expression. Moreover, the EGF-induced KGN proliferation was abrogated, and the activation of downstream signaling was diminished when HOXA7 was knocked down. Overexpression of HOXA7 in SVOG cells had an opposite effect. CONCLUSIONS: Our present study reveals a novel mechanistic role for HOXA7 in modulating granulosa cell proliferation via the regulation of EGFR. This finding contributes to the knowledge of the pro-proliferation effect of HOXA7 in granulosa cell growth and differentiation.
Ovarian localization
Oocyte, Granulosa, Theca, Surface epithelium
Comment
Genes containing the evolutionarily conserved homeodomain sequence encode a family of DNA-binding transcription
factors whose functions are crucial for embryonic development in vertebrates, invertebrates and plants. Adjaye et al 2000 describe the
detection and analysis of transcripts of homeobox-containing genes present in cDNA libraries generated from human
unfertilized oocytes, single cleavage stage embryos (2-cell, 4-cell, 8-cell and blastocyst) and a 10-week old whole
fetus. Using degenerate primers derived from sequences within helix 1 and helix 3 of the highly conserved region of the
Antennapedia-class homeodomain, a 166 bp band was detected in all the cDNA libraries tested. Subcloning of the
oocyte-derived band revealed that it contained a heterogeneous group of 166 bp fragments. Sequence analysis of 40
independent clones demonstrated the presence of HOXA7, HOXD8, and HOXD1 sequences, the ubiquitously expressed
POU family member, OCT1, and HEX, a homeotic gene expressed in haematopoietic cells.
Follicle stages
Primary, Secondary, Antral, Preovulatory
Comment
Cell type- and stage-specific changes in HOXA7 protein expression in human ovarian folliculogenesis: possible role of GDF-9
Ota T et al..
Homeobox (HOX) genes are important transcriptional regulators in development and in adult tissues. A major obstacle to the understanding of their roles in humans has been the lack of well-defined anti-human HOX antibodies. We generated a thoroughly characterized polyclonal rabbit antibody against human HOXA7 and used it to study the distribution, role, and regulation of HOXA7 in human ovarian folliculogenesis and in granulosa cell tumors. Immunohistochemically, follicles were strongly HOXA7-positive compared with stroma. Oocytes expressed little HOXA7. Granulosa cells were predominantly negative in primordial follicles, had uniformly HOXA7-positive nuclei in primary follicles, and, as follicles matured, the subcellular localization of HOXA7 changed from nuclear to predominantly cytoplasmic. HOXA7 was mainly cytoplasmic in theca interna, but completely absent in theca externa. Granulosa cell tumors were mainly HOXA7 positive and, like in preovulatory follicles and theca interna, staining was predominantly cytoplasmic. The change in HOXA7 expression from negative primordial to positive primary follicles suggested a relationship with granulosa cell proliferation. To test this hypothesis, SV40 Tag-immortalized human granulosa cells (SVOG) were double stained with anti-HOXA7 antibody and with Ki-67 as proliferation marker. HOXA7 expression was highest in mitotic cells. In addition, growth differentiation factor-9 (GDF-9), known to be secreted by oocytes in primary human follicles, up-regulated HOXA7 protein, and stimulated proliferation of SVOG, while TGF-beta1 inhibited HOXA7 expression and proliferation. This is the first report on the expression of any HOX gene in human ovarian follicles and granulosa cell tumors. It shows that HOXA7 undergoes cell type- and stage-specific changes during ovarian folliculogenesis, likely regulates granulosa cell proliferation, and in subcellular location differs between proliferating and secretory cells. The increase in HOXA7 protein in response to GDF-9 represents the first demonstration of a possible regulatory role of oocytes in ovarian follicular HOX gene expression.