Limits...
Genetic Syndromes and Genes Involved in the Development of the Female Reproductive Tract: A Possible Role for Gene Therapy.

Connell M, Owen C, Segars J - J Genet Syndr Gene Ther (2013)

Bottom Line: Müllerian and vaginal anomalies are congenital malformations of the female reproductive tract resulting from alterations in the normal developmental pathway of the uterus, cervix, fallopian tubes, and vagina.Modern molecular genetics with study of knock out animal models as well as several genetic syndromes featuring abnormalities of the female reproductive tract have identified candidate genes significant to this developmental pathway.Further emphasizing the importance of understanding female reproductive tract development, recent evidence has demonstrated expression of embryologically significant genes in the endometrium of adult mice and humans.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynecology, Truman Medical Center, Kansas City, Missouri.

ABSTRACT

Müllerian and vaginal anomalies are congenital malformations of the female reproductive tract resulting from alterations in the normal developmental pathway of the uterus, cervix, fallopian tubes, and vagina. The most common of the Müllerian anomalies affect the uterus and may adversely impact reproductive outcomes highlighting the importance of gaining understanding of the genetic mechanisms that govern normal and abnormal development of the female reproductive tract. Modern molecular genetics with study of knock out animal models as well as several genetic syndromes featuring abnormalities of the female reproductive tract have identified candidate genes significant to this developmental pathway. Further emphasizing the importance of understanding female reproductive tract development, recent evidence has demonstrated expression of embryologically significant genes in the endometrium of adult mice and humans. This recent work suggests that these genes not only play a role in the proper structural development of the female reproductive tract but also may persist in adults to regulate proper function of the endometrium of the uterus. As endometrial function is critical for successful implantation and pregnancy maintenance, these recent data suggest a target for gene therapy. Future research will be needed to determine if gene therapy may improve reproductive outcomes for patients with demonstrated deficient endometrial expression related to abnormal gene expression.

No MeSH data available.


Related in: MedlinePlus

Schematic Diagram of Gene Expression in Development of Female Reproductive.Tract: Tissue specific regulation by the Hoxa family homeobox transcription factors are important in the development in the oviducts (Hoxa9), uterus (Hoxa10 and Hoxa11), cervix (Hoxa11 and Hoxa13) and vagina (Hoxa11 and Hoxa13) as shown. Wnt family genes are believed to be involved in the anterior-posterior as well as radial patterning. Specifcally shown here is Wnt7a, which is required for maintenance of Hoxa10 and Hoxa11 expression in the uterus. Also illustrated is the gradient of BMP4 expression, strongest in the vagina and weakest in the uterus. The opposite gradient has been noted for Wnt7a
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4264624&req=5

Figure 1: Schematic Diagram of Gene Expression in Development of Female Reproductive.Tract: Tissue specific regulation by the Hoxa family homeobox transcription factors are important in the development in the oviducts (Hoxa9), uterus (Hoxa10 and Hoxa11), cervix (Hoxa11 and Hoxa13) and vagina (Hoxa11 and Hoxa13) as shown. Wnt family genes are believed to be involved in the anterior-posterior as well as radial patterning. Specifcally shown here is Wnt7a, which is required for maintenance of Hoxa10 and Hoxa11 expression in the uterus. Also illustrated is the gradient of BMP4 expression, strongest in the vagina and weakest in the uterus. The opposite gradient has been noted for Wnt7a

Mentions: Knock out mouse models have provided insight into the signaling molecules and transcription factors essential for Müllerian duct formation [10-12]. Development of the Müllerian ducts is considered a triphasic process consisting of initiation, invagination, and elongation [7]. Phase one involves coelomic epithelial cells being specified for a Müllerian duct fate. Mechanisms controlling this first phase have not been fully elucidated, however specification of cells can be recognized by the presence of Lim homeobox 1 (Lim1). Lim1 is key to the development of the Müllerian duct epithelium as absence of Lim1 in mice leads to a phenotype lacking oviducts, uterus, and an upper vagina [13]. Following initiation, invagination occurs through the expression of wingless-type MMTV integration site family, member 4 (WNT4) [13]. This gene is known to antagonize the testis-determining factor and play a critical role in both the control of female development and the prevention of testes formation. This second phase ends when the invaginating Müllerian ducts contact the Wolffian ducts. The first two phases have been shown to be Wolffian duct independent [14]. On the contrary, the third phase of elongation requires the maintenance of the Wolffian ducts [15]. Conditional inactivation of Lim1 has been associated with Wolffian duct regression and subsequently results in incomplete development of the Müllerian ducts [14]. The elongation phase also involves proliferation of cells at the mesoepithelial tip of the Müllerian ducts which requires the presence of the Wolffian ducts through Wnt9b signaling which is associated with regulation of cell fate and patterning during embryogenesis [7, 16]. Paired box 2 (Pax2) is another gene that has been shown necessary for the second phase of Mullerian duct development. Knock out mouse models for Pax2 lack both a genital tract and kidneys in male and female animals [17]. It has been demonstrated in these knock out mice that coelomic epithelium invaginates, however the Wolffian ducts degenerate and hence the Müllerian ducts do not elongate leading to failure of the third phase [17]. Empty spiracles homeobox 2 (Emx2) is expressed in epithelial components of the urogenital system and absence of Emx2 leads to a complete absence of the urogenital system, which is obviously essential for normal development of the female reproductive outflow tract [18]. Emx2 mutant mice show abnormal expression of Lim1, Pax2, and Wnt4 in the intermediate mesoderm [18]. These related mechanisms suggest an underlying genetic pathway for the formation of the Müllerian ducts. Roles for the previously mentioned genes have been mostly elucidated; however Müllerian duct formation is not completely understood and other key genes in the pathway continue to be discovered. Retinoic acid appears to be involved in the anterior posterior patterning and in female reproductive tract development but few details are known. In the mouse model, compound mutations of retinoic acid receptors either demonstrate absence of the entire female reproductive tract or only the caudal portions [19, 20]. The POU domain-containing transcription factor 2 (Tcf2) gene has been shown in mouse models to be expressed during the earliest steps of female reproductive tract formation [21]. Mutations of TCF2 in humans have been associated with bicornuate and didelphic uteri [22]. Similar abnormalities have been described in discs, large homolog 1 (Dlgh1) mice, who experience aplasia of the cervix and vagina from failed lateral fusion of the Müllerian ducts [23]. Transcriptional cofactors dachshund homolog 1 and 2 (Dach1 and Dach2) seem to fit within this developmental cascade as the double knock out mouse model shows complete failure to develop Müllerian duct derivatives [24]. Following Müllerian duct formation, differentiation occurs along an antero-posterior (A-P) and radial axis. This includes the formation of the oviducts, uterus, cervix, and vagina. This occurs through interactions between the Müllerian duct epithelium and the surrounding mesenchyme [25]. This A-P patterning establishes histologically distinct segmental boundaries. The anterior boundary occurs between the oviduct and uterine body, and the posterior boundary is between the uterus and cervix [25]. This patterning is primarily regulated by Hoxa family homeobox transcription factors. Hoxa9, Hoxa10, Hoxa11, and Hoxa13 are expressed uniformly along the A-P axis (Figure 1). Hoxa9 is expressed in the oviduct whereas Hoxa10 and Hoxa11 are expressed in the uterus. Hoxa11 and Hoxa13 can be found in the cervix and anterior vagina [26]. Hoxa10 and Hoxa11, as expected, are required for patterning and differentiation of the uterus and their expression patterns overlap during embryogenesis [27]. For example, Hoxa10 mutants have demonstrated homeotic transformation of the anterior part of the uterus into oviduct like structures leading to reduced fertility [28]. Hoxa11 has been shown to be necessary for proper organization of uterine stroma where loss of this gene leads to thinner, shorter uteri and no endometrial glands suggesting a more anterior phenotype [11, 29]. On the contrary, an alternative study demonstrated absence of uterosacral ligaments (USL) in Hoxa11 mice suggesting a more posterior phenotype [30]. Hoxa13 mice show agenesis of the distal portion of the Müllerian ducts indicating a role for Hoxa13 not only in differentiation but also in the formation of Müllerian ducts [31]. Temporal and spatial variation in expression of the Hoxa family genes may explain the diversity of uterine shapes seen that perhaps result from different degrees of Müllerian duct fusion [31]. Several genes aside from the Hoxa family genes have also been shown to regulate Müllerian duct differentiation. Wnt family genes appear to control the A-P and radial patterning. Wnt7a mutant mice exhibit several abnormalities including shortened and uncoiled oviducts, hypoplastic uterine horns, and a vaginal septum [32]. In addition, Wnt7a mutant mice have been shown to have endometrial gland agenesis, disorganized myometrium, a reduction in the stromal compartment of the uterus and posterior appearing uteri [32]. In these mice, the posterior aspect of the oviduct resembles the uterus, and the uterus has similar characteristics to the vagina [32]. Wnt7a appears to be required for the maintenance of Hoxa10 and Hoxa11 as knockout of Wnt7a has shown decreased expression of Hoxa10 and Hoxa11 [32]. Wnt5a also appears to be important in this pathway as mice die at birth secondary to improper A-P axis development [33]. Elegant grafting models have allowed for more precise study of the role of Wnt5a. Wnt5a mutant mice were shown to have short, coiled uterine horns; but lack defined cervical and vaginal structures [33]. This phenotype is similar to that of Hoxa13 mutants. Wnt5a mutants were also shown to have absent uterine glandular formation [33]. Both knock out models of Wnt5a and Wnt7a suggested an important role in glandular genesis. Both Wnt5a and Wnt7a are required for correct glandular genesis as these genes are expressed in the uterine stroma and uterine epithelium respectively [32, 33]. In areas where uterine epithelial invaginations occur, Wnt7a was down regulated. Wnt5a appears to be critical in this down regulation leading to endometrial glandular formation [33]. This highlights the role of epithelial-mesenchymal interaction required for uterine development [34]. As noted above, knockout of Wnt5a was shown to be associated with glandular agenesis, however the luminal epithelium was noted to be intact [33]. Catenin (cadherin-associated protein), beta 1 (Ctnnb1) produces the protein β-catenin and is a downstream effector of the Wnt family genes. Knock out of this protein leads to absence of uterine glandular tissue and an epithelium that resembles that of the vagina [35]. Finally, forkhead box A2 (Foxa2) has been identified as an important regulatory gene in gland formation as ablation of Foxa2 leads to glandular agenesis [36]. The exact factors that interact upstream or downstream of Foxa2 are not currently known, but no change in Wnt5a or Wnt7a was observed in this ablation model [36]. However, Foxa2 expression was noted to be absent in the Wnt7a conditional knockout, suggesting that Foxa2 is downstream of Wnt7a [37]. The pathways that orchestrate Müllerian duct formation and differentiation are obviously complex. Several of the underlying genetic mechanisms have been described, but more research is needed to gain a fundamental understanding of the genetic basis of the female reproductive tract.


Genetic Syndromes and Genes Involved in the Development of the Female Reproductive Tract: A Possible Role for Gene Therapy.

Connell M, Owen C, Segars J - J Genet Syndr Gene Ther (2013)

Schematic Diagram of Gene Expression in Development of Female Reproductive.Tract: Tissue specific regulation by the Hoxa family homeobox transcription factors are important in the development in the oviducts (Hoxa9), uterus (Hoxa10 and Hoxa11), cervix (Hoxa11 and Hoxa13) and vagina (Hoxa11 and Hoxa13) as shown. Wnt family genes are believed to be involved in the anterior-posterior as well as radial patterning. Specifcally shown here is Wnt7a, which is required for maintenance of Hoxa10 and Hoxa11 expression in the uterus. Also illustrated is the gradient of BMP4 expression, strongest in the vagina and weakest in the uterus. The opposite gradient has been noted for Wnt7a
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264624&req=5

Figure 1: Schematic Diagram of Gene Expression in Development of Female Reproductive.Tract: Tissue specific regulation by the Hoxa family homeobox transcription factors are important in the development in the oviducts (Hoxa9), uterus (Hoxa10 and Hoxa11), cervix (Hoxa11 and Hoxa13) and vagina (Hoxa11 and Hoxa13) as shown. Wnt family genes are believed to be involved in the anterior-posterior as well as radial patterning. Specifcally shown here is Wnt7a, which is required for maintenance of Hoxa10 and Hoxa11 expression in the uterus. Also illustrated is the gradient of BMP4 expression, strongest in the vagina and weakest in the uterus. The opposite gradient has been noted for Wnt7a
Mentions: Knock out mouse models have provided insight into the signaling molecules and transcription factors essential for Müllerian duct formation [10-12]. Development of the Müllerian ducts is considered a triphasic process consisting of initiation, invagination, and elongation [7]. Phase one involves coelomic epithelial cells being specified for a Müllerian duct fate. Mechanisms controlling this first phase have not been fully elucidated, however specification of cells can be recognized by the presence of Lim homeobox 1 (Lim1). Lim1 is key to the development of the Müllerian duct epithelium as absence of Lim1 in mice leads to a phenotype lacking oviducts, uterus, and an upper vagina [13]. Following initiation, invagination occurs through the expression of wingless-type MMTV integration site family, member 4 (WNT4) [13]. This gene is known to antagonize the testis-determining factor and play a critical role in both the control of female development and the prevention of testes formation. This second phase ends when the invaginating Müllerian ducts contact the Wolffian ducts. The first two phases have been shown to be Wolffian duct independent [14]. On the contrary, the third phase of elongation requires the maintenance of the Wolffian ducts [15]. Conditional inactivation of Lim1 has been associated with Wolffian duct regression and subsequently results in incomplete development of the Müllerian ducts [14]. The elongation phase also involves proliferation of cells at the mesoepithelial tip of the Müllerian ducts which requires the presence of the Wolffian ducts through Wnt9b signaling which is associated with regulation of cell fate and patterning during embryogenesis [7, 16]. Paired box 2 (Pax2) is another gene that has been shown necessary for the second phase of Mullerian duct development. Knock out mouse models for Pax2 lack both a genital tract and kidneys in male and female animals [17]. It has been demonstrated in these knock out mice that coelomic epithelium invaginates, however the Wolffian ducts degenerate and hence the Müllerian ducts do not elongate leading to failure of the third phase [17]. Empty spiracles homeobox 2 (Emx2) is expressed in epithelial components of the urogenital system and absence of Emx2 leads to a complete absence of the urogenital system, which is obviously essential for normal development of the female reproductive outflow tract [18]. Emx2 mutant mice show abnormal expression of Lim1, Pax2, and Wnt4 in the intermediate mesoderm [18]. These related mechanisms suggest an underlying genetic pathway for the formation of the Müllerian ducts. Roles for the previously mentioned genes have been mostly elucidated; however Müllerian duct formation is not completely understood and other key genes in the pathway continue to be discovered. Retinoic acid appears to be involved in the anterior posterior patterning and in female reproductive tract development but few details are known. In the mouse model, compound mutations of retinoic acid receptors either demonstrate absence of the entire female reproductive tract or only the caudal portions [19, 20]. The POU domain-containing transcription factor 2 (Tcf2) gene has been shown in mouse models to be expressed during the earliest steps of female reproductive tract formation [21]. Mutations of TCF2 in humans have been associated with bicornuate and didelphic uteri [22]. Similar abnormalities have been described in discs, large homolog 1 (Dlgh1) mice, who experience aplasia of the cervix and vagina from failed lateral fusion of the Müllerian ducts [23]. Transcriptional cofactors dachshund homolog 1 and 2 (Dach1 and Dach2) seem to fit within this developmental cascade as the double knock out mouse model shows complete failure to develop Müllerian duct derivatives [24]. Following Müllerian duct formation, differentiation occurs along an antero-posterior (A-P) and radial axis. This includes the formation of the oviducts, uterus, cervix, and vagina. This occurs through interactions between the Müllerian duct epithelium and the surrounding mesenchyme [25]. This A-P patterning establishes histologically distinct segmental boundaries. The anterior boundary occurs between the oviduct and uterine body, and the posterior boundary is between the uterus and cervix [25]. This patterning is primarily regulated by Hoxa family homeobox transcription factors. Hoxa9, Hoxa10, Hoxa11, and Hoxa13 are expressed uniformly along the A-P axis (Figure 1). Hoxa9 is expressed in the oviduct whereas Hoxa10 and Hoxa11 are expressed in the uterus. Hoxa11 and Hoxa13 can be found in the cervix and anterior vagina [26]. Hoxa10 and Hoxa11, as expected, are required for patterning and differentiation of the uterus and their expression patterns overlap during embryogenesis [27]. For example, Hoxa10 mutants have demonstrated homeotic transformation of the anterior part of the uterus into oviduct like structures leading to reduced fertility [28]. Hoxa11 has been shown to be necessary for proper organization of uterine stroma where loss of this gene leads to thinner, shorter uteri and no endometrial glands suggesting a more anterior phenotype [11, 29]. On the contrary, an alternative study demonstrated absence of uterosacral ligaments (USL) in Hoxa11 mice suggesting a more posterior phenotype [30]. Hoxa13 mice show agenesis of the distal portion of the Müllerian ducts indicating a role for Hoxa13 not only in differentiation but also in the formation of Müllerian ducts [31]. Temporal and spatial variation in expression of the Hoxa family genes may explain the diversity of uterine shapes seen that perhaps result from different degrees of Müllerian duct fusion [31]. Several genes aside from the Hoxa family genes have also been shown to regulate Müllerian duct differentiation. Wnt family genes appear to control the A-P and radial patterning. Wnt7a mutant mice exhibit several abnormalities including shortened and uncoiled oviducts, hypoplastic uterine horns, and a vaginal septum [32]. In addition, Wnt7a mutant mice have been shown to have endometrial gland agenesis, disorganized myometrium, a reduction in the stromal compartment of the uterus and posterior appearing uteri [32]. In these mice, the posterior aspect of the oviduct resembles the uterus, and the uterus has similar characteristics to the vagina [32]. Wnt7a appears to be required for the maintenance of Hoxa10 and Hoxa11 as knockout of Wnt7a has shown decreased expression of Hoxa10 and Hoxa11 [32]. Wnt5a also appears to be important in this pathway as mice die at birth secondary to improper A-P axis development [33]. Elegant grafting models have allowed for more precise study of the role of Wnt5a. Wnt5a mutant mice were shown to have short, coiled uterine horns; but lack defined cervical and vaginal structures [33]. This phenotype is similar to that of Hoxa13 mutants. Wnt5a mutants were also shown to have absent uterine glandular formation [33]. Both knock out models of Wnt5a and Wnt7a suggested an important role in glandular genesis. Both Wnt5a and Wnt7a are required for correct glandular genesis as these genes are expressed in the uterine stroma and uterine epithelium respectively [32, 33]. In areas where uterine epithelial invaginations occur, Wnt7a was down regulated. Wnt5a appears to be critical in this down regulation leading to endometrial glandular formation [33]. This highlights the role of epithelial-mesenchymal interaction required for uterine development [34]. As noted above, knockout of Wnt5a was shown to be associated with glandular agenesis, however the luminal epithelium was noted to be intact [33]. Catenin (cadherin-associated protein), beta 1 (Ctnnb1) produces the protein β-catenin and is a downstream effector of the Wnt family genes. Knock out of this protein leads to absence of uterine glandular tissue and an epithelium that resembles that of the vagina [35]. Finally, forkhead box A2 (Foxa2) has been identified as an important regulatory gene in gland formation as ablation of Foxa2 leads to glandular agenesis [36]. The exact factors that interact upstream or downstream of Foxa2 are not currently known, but no change in Wnt5a or Wnt7a was observed in this ablation model [36]. However, Foxa2 expression was noted to be absent in the Wnt7a conditional knockout, suggesting that Foxa2 is downstream of Wnt7a [37]. The pathways that orchestrate Müllerian duct formation and differentiation are obviously complex. Several of the underlying genetic mechanisms have been described, but more research is needed to gain a fundamental understanding of the genetic basis of the female reproductive tract.

Bottom Line: Müllerian and vaginal anomalies are congenital malformations of the female reproductive tract resulting from alterations in the normal developmental pathway of the uterus, cervix, fallopian tubes, and vagina.Modern molecular genetics with study of knock out animal models as well as several genetic syndromes featuring abnormalities of the female reproductive tract have identified candidate genes significant to this developmental pathway.Further emphasizing the importance of understanding female reproductive tract development, recent evidence has demonstrated expression of embryologically significant genes in the endometrium of adult mice and humans.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynecology, Truman Medical Center, Kansas City, Missouri.

ABSTRACT

Müllerian and vaginal anomalies are congenital malformations of the female reproductive tract resulting from alterations in the normal developmental pathway of the uterus, cervix, fallopian tubes, and vagina. The most common of the Müllerian anomalies affect the uterus and may adversely impact reproductive outcomes highlighting the importance of gaining understanding of the genetic mechanisms that govern normal and abnormal development of the female reproductive tract. Modern molecular genetics with study of knock out animal models as well as several genetic syndromes featuring abnormalities of the female reproductive tract have identified candidate genes significant to this developmental pathway. Further emphasizing the importance of understanding female reproductive tract development, recent evidence has demonstrated expression of embryologically significant genes in the endometrium of adult mice and humans. This recent work suggests that these genes not only play a role in the proper structural development of the female reproductive tract but also may persist in adults to regulate proper function of the endometrium of the uterus. As endometrial function is critical for successful implantation and pregnancy maintenance, these recent data suggest a target for gene therapy. Future research will be needed to determine if gene therapy may improve reproductive outcomes for patients with demonstrated deficient endometrial expression related to abnormal gene expression.

No MeSH data available.


Related in: MedlinePlus