mutation cycle of female reproductive system
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positional identity that leads to the proper partitioning and adult identity of the female reproductive track. Abnormalities in reproductive tract development can be caused by HOX gene mutations or altered HOX gene expression. Diethylstilbestrol (DES) and other endocrine disruptors cause Müllerian defects by changing HOX gene expression. HOX genes are also essential regulators of adult endometrial development. Regulated HOXA10 and HOXA11 expression is necessary for endometrial receptivity; decreased HOXA10 or HOXA11 expression leads to decreased implantation rates. Alternation of HOXA10 and HOXA11 expression has been identified as a mechanism of the decreased implantation associated with endometriosis, polycystic ovarian syndrome, leiomyoma, polyps, adenomyosis, and hydrosalpinx. Alteration of HOX gene expression causes both uterine developmental abnormalities and impaired adult endometrial development that prevent implantation and lead to female infertility.
HOX genes comprise a family of regulatory molecules that encode highly conserved transcription factors. In the past several decades, molecular and genetic evidence indicates that HOX genes are expressed along anterior–posterior axes and control morphogenesis and cell differentiation during normal embryonic axial development; this mechanism for assigning differential identity along previously uniform axes is used in species as diverse as Drosophila and humans (McGinnis and Krumlauf 1992). HOX genes have a similar role in the specification of the developmental fate in individual regions of the female reproductive tract, where they regulate developmental axis in the embryonic period. HOX genes also give specific identity to the developing endometrium during the menstrual cycle in adults. The cyclic growth of endometrium is dependent on the ordered production of estrogen and progesterone. HOX gene expression is regulated by sex steroids, and this regulated expression plays an important role in endometrial development and endometrial receptivity (Taylor et al. 1997, 1998, 1999b). Here, we review the role of HOX genes, specifically the HOXA/Hoxa genes, in reproductive tract development, endometrial cyclic growth and embryo implantation, and the alterations in HOXA/Hoxa gene expression that can lead to infertility.
HOX GENES AND THEIR ROLE IN THE BODY PLAN
HOX Genes
Homeobox genes (as known as HOX genes) comprise a group of highly conserved genes that are essential regulators of anterior–posterior (A–P) axial pattern development. In 1978, the relationship between the location of a homeotic gene and positional development identity was first recognized in Drosophila (Lewis 1978). Six years later, the HOX genes were cloned and sequenced in the fruit fly Drosophila melanogaster (McGinnis et al. 1984a,b; Scott and Weiner 1984). Since then, multiple HOX genes have been identified in many species, including humans. HOX genes encode proteins that act as transcription factors. In each of the HOX genes, a 183-bp highly conserved sequence was identified, which encodes a 61-amino acid region, called the homeodomain (HD). Structural analyses have shown that the HD can self-fold, and form a structural motif called a “helix-turn-helix motif.” Through this motif, the HD, a DNA binding domain, recognizes a typical core DNA sequence, typically TAAT or TTAT, and regulates the expression of target genes, many of which play a role in axial development (Gehring et al. 1994; Krumlauf 1994; Gruschus et al. 1999; Passner et al. 1999).
Like all other insects, Drosophila has eight HOX genes, which are clustered into two complexes in close proximity, the antennapedia (Ant-C) complex and bithorax (Bx-C) complex. In mice and humans, Hox/HOX genes are clustered into four unlinked genomic loci, Hox a-d (mouse) or HOX A-D (human); each locus contains nine to 13 genes and all four clusters contain a total of 39 HOX genes. Those four paralogues, classified by sequence similarity, are located on chromosomes 6, 11, 15, and 2 in mice and chromosomes 7, 17, 12, and 2 in humans. The clustered HOX genes are believed to have arisen from gross duplication of a single common ancestral cluster. Presently, none of the paralogues have 13 genes, so some duplicated genes must have been lost during the course of evolution (Krumlauf 1994).