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| Fetal Gonads, Sexual Dimorphism, and ß-catenin |
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| Science - Biological Sciences | |||||||
| TS-Si News Service | |||||||
| Monday, 17 November 2008 21:00 | |||||||
 Champaign, IL, USA. The interplay of certain genes and non-coding DNA are essential to the effective growth and development of most organ systems in the body. That is true for early stages of sexual development. Studies of specific genes and coding proteins are important building blocks for scientific understanding. They are subject in turn to more nuanced intrpretations that account for the influence of the genome, the sum total of DNA, inlusing non-coding proteins and error-correction mechanisms.
For example, scientists recently identfied an essential gene that is vital to female — but not male — differentiation. The mechanisms that determine whether an organism will be female or male are more complex than a simple accounting of "X" and "Y" genes on the chromosome. Following conception, and near the beginning of human development, the potential sexual organs of all embryos are in a state of primordium — the simplest set of initial conditions capable of triggering growth.
At first, the sexual organs look the same, whether or not their evenual development is suitable for female or male development. In fact, potential females and males have a primordium in common, the foundation for both ovary and testis. Humphrey Yao, a professor of veterinary biosciences at the University of Illinois notes that “Only at a certain stage of development does this primordium start to follow a different path.” A study by Yao and colleagues from the University of Illinois and the University of Texas provide improved clarity on the process of sexual differentiation. Their findings appear in Human Molecular Genetics.
Sex-Specific Roles of ß-catenin in Mouse Gonadal Development. Chia-Feng Liu, Nathan Bingham, Keith Parker, and Humphrey H-C Yao. Hum. Mol. Genet. Advance Access published on November 3, 2008; doi: 10.1093 / hmg / ddn362.
 Testosterone (T) is a steroid hormone from the androgen group. It is found in numerous animals, with the largest amounts secreted in the Leydig cells of male testes. Testosterone is also synthesized in far smaller quantities in women by the ovarian sheath (thecal cells) and placenta. Small amounts are also secreted by the zona reticularis in both sexes by the adrenal glands.
On average, an adult human male body produces about 8-10 times more testosterone than a female. Testosterone plays key roles in health and well-being for both males and females. Examples include enhanced energy, libido, immune function, and protection against osteoporosis.
Like other steroid hormones, T is derived from cholesterol. Like most hormones, it is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone binding globulin (SHBG).
VIRILIZING AND ANABOLIC EFFECTS ON HUMANS
In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone can include a number of noticeable effects.
Anabolic effects. These include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation.
Virilizing effects. These include maturation of the sex organs, particularly the penis and the formation of the scrotum in unborn children, and after birth (usually at puberty) a deepening of the voice, growth of the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics.
Age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone. Most of the prenatal androgen effects occur between 7 and 12 weeks of gestation. Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4-6 months of age. The function of this rise in humans is unknown.
Genital virilization. These include midline fusion, phallic urethra, scrotal thinning and rugation, and phallic enlargement. The role of testosterone is far smaller than that of Dihydrotestosterone. Also, testosterone affects the development of prostate and seminal vesicles.
SYNTHESIS
Testosterone can be synthesized in large quantities. There are two possible modifications that provide capabilities for either injection or oral intake.
Esterification. The C-17 hydroxyl group testosterone can be esterified, or altered, by the substitution of an acid group for the hydroxyl group at the C17 position. Esterification lowers the water solubility of the molecule and increases its lipid solubility, permitting a sterile oil-based injectible with testosterone to form a “depot” in the muscle, from which it is gradually released.
Alkylation. Testosterone can be alkylated by substituting of an ethyl or methyl group for the hydroxyl group. Alkylation permits oral steroids, the so-called “17-aa” or alkylated family of androgens such as methyltestosterone, which can be taken up by the digestive tract, and so be easily administered in pill form. However, this outline fails to account for some rare cases of individuals who developed testes even though they had two X chromosomes and no Y chromosome (or SRY gene). This led to the so-called “Z” hypothesis. This is a male-centric view that claims testes development as the default pathway in mamallian sexual development.
According to this hypothesis, an unknown gene or process, called “Z”, could disrupt this pathway and lead to the development of ovaries. The “Z” hypothesis explained why SRY appeared essential for testes development. When it is present, SRY suppresses “Z” and allows the default option (development of testes) to occur. Elevated to the status of a complex and ambiguous theory, it did not readily generate experiments that could lead to confirmation or denial.
The hypothesis, as stated, did not directly address whether females or males are the default, but was widely heralded as doing just that in the public press and some psychosocial circles. Critics noted the reversibility of the hypothesis: it could readily be used to explain the specifics of male sexual differentiation from a female default. Many critics subsequently abandoned "Z" and pursued other approaches that more formally explore signaling pathways.
Humphrey Yao and graduate student Chia-Feng Liu decided on a closer investigation into a particular molecule known to be involved in transforming the primordium into testis or ovary. Called the beta-catenin protein, the molecule is an important regulator of cell proliferation and differentiation.
Yao and Liu knew that other proteins also were particularly critical to the development of ovaries. Mice that lacked the genes for a signaling protein, known as Wnt4, or another secreted protein, called R-spondin1, experienced a partial female-to-male sex reversal: They formed ovaries, but with male characteristics, such as blood-vessel structures like those in testes. Humans with mutations in their WNT4 and R-spondin1 genes had similar malformations of the sex organs.
To determine whether beta-catenin had a role in forming the ovaries, the researchers developed a mouse embryo in which the beta-catenin gene could be shut off at the earliest stage of development of the gonads while remaining functional in other organs.
“To our surprise, the ovaries still formed,” Yao said. But male sexual structures also appeared, creating an amalgamation of male and female sexual structures that looked very much like those produced when the Wnt4 or R-spondin1 genes were mutated or missing. “That tells us very conclusively that beta-catenin is an internal regulator of this pathway,” Yao said.
To see how the absence of beta-catenin would affect testes formation, the researchers repeated the experiment in embryos in the early stages of testes development. “When we looked at the testes without beta-catenin,” Yao said, “they developed just fine.”
The results were so unexpected that the researchers conducted the experiment again and again to test their findings. “When I looked at the results in the testes I couldn’t believe it. How could such an important gene like beta-catenin function differently in males and females?” Yao said.
When beta-catenin acts as a transcription factor it goes into the nucleus of the cell to interact with the DNA. The proteins, Wnt4 and R-spondin1 (and another one, called follistatin, which is also an important player in this pathway), are all secreted proteins. They are emitted from the cell, Yao said, and yet it appears that their production or secretion relies on an intracellular protein, beta-catenin.
“Wnt4, R-spondin1, follistatin — these genes all code for secreted proteins,” Yao said. “How does the cell know to respond to this signal? And how can secreted factors change the fate of an organism?”
Yao said his team’s findings provided some support for the “Z” hypothesis, with beta-catenin acting as a vital intermediary in a pathway that includes Wnt4 and R-spondin1 to suppress the development of male sex organs.
However, the research was limited to genetic interactions with supressing proteins. The research has a potential to stimulate additional research that examines the role of genomic mechanisms for error-regulation.
FundingThis study was supported in part by the National Institutes of Health (NIH) and the March of Dimes Foundation.
CitationSex-Specific Roles of ß-catenin in Mouse Gonadal Development. Chia-Feng Liu, Nathan Bingham, Keith Parker, and Humphrey H-C Yao. Hum. Mol. Genet. Advance Access published on November 3, 2008; doi: 10.1093 / hmg / ddn362.
Abstract Sexually dimorphic development of the gonads is controlled by positive and negative regulators produced by somatic cells. Many Wnt ligands, including ones that signal via the canonical ß-catenin pathway, are expressed in fetal gonads. ß-catenin, a key transcriptional regulator of the canonical Wnt pathway and an element of the cell adhesion complex, is essential for various aspects of embryogenesis. To study the involvement of ß-catenin in sex determination, we ablated ß-catenin specifically in the SF1-positive population of somatic cells. Although ß-catenin was present in gonads of both sexes, it was necessary only for ovarian differentiation but dispensable for testis development. Loss of ß-catenin in fetal testes did not affect Sertoli cell differentiation, testis morphogenesis, or masculinization of the embryos. However, we observed molecular and morphological defects in ovaries lacking ß-catenin, including formation of testis-specific coelomic vessel, appearance of androgen-producing adrenal-like cells, and loss of female germ cells. These phenotypes were strikingly similar to those found in the R-spondin1 (Rspo1) and Wnt4 knockout ovaries. In the absence of ß-catenin, expression of Wnt4 was downregulated while that of Rspo1 was not affected, placing ß-catenin as a component in between Rspo1 and Wnt4. Our results demonstrate that ß-catenin is responsible for transducing sex-specific signals in the SF1-positive somatic cell population during mouse gonadal development.
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| Last Updated on Monday, 17 November 2008 22:05 |
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