Deletion of the Wt1 gene causes changes in the reproductive organs of mice: a decisive gene in the biology of sex

Removing the wt1 gene during the early stages of embryonic reproductive organ formation leads to differences in sex development in adult mice, according to an article published in the journal PLOS Genetics and led by the lecturer Ofelia Martínez-Estrada, from the Faculty of Biology and the Biomedicine Research Institute (IRBio) of the University of Barcelona.

Among the participants in the article are the experts Francesc X. Soriano, from the Department of Cell Biology, Physiology and Immunology, and the Institute of Neuroscience of the UB (UBNeuro), and Manuel Reina, from the same department and the Celltec UB research group.

A decisive gene in the biology of sex

The wt1 gene of Wilms tumorigen is expressed during mammalian embryonic development in many organs and tissues (genitourinary system, spleen, heart, diaphragm, etc.). In the scientific literature, the mutations of the Wt1 gene have been related to some pathologies – syndromes such as Denys-Drash, Frasier and Meacham’s – including genitourinary defects and differences in sex development (such as ambiguous genitalia or abnormal development of the gonads).

These differences in sexual development are congenital disorders in which the development of the chromosomal, gonadal, or anatomical sex is atypical. Despite efforts to understand the genetic factors that cause these changes, in many cases the origin is unknown and it is difficult to give an accurate diagnosis to affected people.

Mouse models with modifications in the expression of key genes in sex development are being developed as decisive elements for studying this complex process in mammals. Therefore, in recent years, new genetic tools have been generated in murine mutated models to study various aspects of the biology of the WT1 gene.

As part of the study, the team presents a new genetically modified mouse model (Wt1KO) which revealed the importance of the Wt1 gene in the initial differentiation of the early-stage embryonic gonad and its impact on the formation of the reproductive system of adult mice. According to the conclusions, female and male Wt1KO mutated mice – unable to express the Wt1 gene in reproductive tracts from the early stages of formation – exhibited ambiguous sex organs and their gonads remained in an undifferentiated stage.

“In this study, we argue that the wt1 gene is required to activate the pathways that determine male and female development, since embryonic mutated gonads do not express the specific genes for each genetic program,” says lecturer Ofelia Martínez-Estrada of the Department of Cell Biology, Physiology and Immunology of the University Library.

Until now, it was difficult to understand the functions of the WT1 transcription factor – encoded by the said gene – during early differentiation of the gonad and its impact on adult sex development. The lack of development in the gonads or in the genital tract (gonadal agenesis) and the embryonic lethality demonstrated in Wt1KO mutated mice hindered the progress of research to elucidate the role of this gene in these developmental processes.

“Based on the results obtained, we propose that this mouse model could contribute to improving the knowledge about the functions of the WT1 gene in some populations of progenitor cells in different organs and tissues, as well as the importance of these cell populations in the formation of organs in adults,” concludes lecturer Ofelia Martínez-Estrada.

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