Assisted Reproduction and Infertility


Genetic Basis for the Development of Müllerian Abnormalities – A Review of Current Evidence


Panagiotis Christopoulos,1 Georgia Fotopoulou,1 Maria Gazouli2 and George Creatsas1 1. Second Department of Obstetrics and Gynaecology, ‘Aretaieion’ Hospital; 2. Laboratory of Biology, Medical School, University of Athens


Abstract


In recent years, research has proved that a number of genes are responsible for malformations of the female reproductive tract. This article discusses the emerging genetic pathways that might be involved in the formation of a normal or abnormal female reproductive system. As several questions of major importance remain to be answered, more experiments are needed to bring to light the genetic pathways of congenital anomalies of the female genital tract.


Keywords Genes, embryology, genetics, mutation, congenital anomalies, female reproductive system


Disclosure: The authors have no conflicts of interest to declare. Received: 6 June 2010 Accepted: 5 July 2010 Citation: European Obstetrics & Gynaecology, 2010;5:7–12 Correspondence: Panagiotis Christopoulos, 1 Hariton Str, Kifissia, 14564 Athens, Greece. E: dr_christopoulos@yahoo.gr


In recent years, researchers have shown great interest in the investigation of a probable genetic basis of the events that take place during the development of the female reproductive tract. The indications are that the absence of a number of genes may be responsible for malformations. This article discusses the emerging genetic pathways that might be involved in the formation of a normal or abnormal female reproductive system.


Molecular Genetics


Genes responsible for the organogenesis of the female reproductive tract can be distinguished into those participating in the formation of the reproductive ducts; the development of persistent Müllerian ducts and the degeneration of Müllerian ducts in males.


Genes Responsible for


Formation of the Reproductive Ducts Wnt genes (Wnts) encode intercellular growth and differentiation factors that regulate steps in the development of the central nervous system, midbrain, kidneys, limbs and female reproductive tract.1


biosynthesis of gonadal androgens.5–7 Wnt4 deficiency results in sex-


reversal of the XX gonad, whereas the XY gonad remains unaffected.7


As invagination for tubulogenesis of the Müllerian duct


does not occur in Wnt4 mutants, it is evident that Wnt4 plays an important role in the invagination but not the specification of the Müllerian ducts.8


It is generally believed that the autosomal gene Sox9 induces the development of testis when the sex-determining region Y (SRY) is absent. Sox9-/- XY mice were found to lack testis cord and Leydig cells. They had a complete sex reversal, expressed by the ovarian markers Wnt4 and Fox12.9


Wnts


are known to guide epithelial to mesenchymal interactions via glycoproteins that are homologous to the Drosophila segment- polarity gene wingless (wg).2


Several pathways have been proposed


as being involved in the cascade of events following Wnt activation,3 such as the activation of a Wnt1–green fluorescent protein (GFP) fusion protein and the interaction of a cytoplasmic beta-catenin with the Lef/Tcf family of transcription factors in the nucleus.4


The Wnt4 gene is expressed in the gonads of both sexes before sex differentiation and is involved in the initial steps of the formation of the Müllerian ducts.5,6 gonad,6


Subsequently, it is downregulated in the male provoking regression of the Müllerian ducts. Additionally, it is


claimed that Wnt4 participates in sex-specific cell migration events, the formation of sex-specific vasculature and suppression of the


© TOUCH BRIEFINGS 2010


The Wnt5a-mutant female shows normal development of the posterior derivatives of the female reproductive tract.10


The Wnt5a


gene, in co-operation with the Wnt7a, Hoxa10 and Hoxa11 genes, is responsible for the oestrogen-dependent changes in the uterine stroma.10


It is known that the Wnt, hedgehog (Hh) and Hoxa genes co-operate to ensure the anteroposterior differentiation and radial pattern of uterine tissues. Exposure of neonatal gilts to oestrogens for two weeks after birth resulted in hypoplastic adult porcine uteri and altered temporospatial patterns of the Wnt, Hh and Hoxa genes.11


The


phenotypes of the loss-of-function mutations of Wnt5a and Wnt7a are similar to those of Hox genes.10,12


7


that Wnt4 is essential, together with SRY, for normal Sertoli cell differentiation. However, its level of expression has to be directly or indirectly decreased by Sox9 in order to achieve normal testicular development.


the decrease in expression of Wnt4 (E11.0–E11.5) and Fox12 is dependent mainly on Sox9 and not the SRY. Barrionuevo et al.9 concluded that in humans XY sex reversal caused by Sox9 haploinsufficiency might be due to the inability of the amount of Sox9 present to downregulate Wnt4. Nevertheless it has been noted9


It can therefore be assumed that


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