The elusive action of sex-determining genes: mitochondria to the rescue?

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Abstract

According to the accepted dogma of mammalian sex determination, the Y-linked gene SRY initiates male development by inducing hitherto uncommitted somatic cells of the fetal gonad to develop into Sertoli cells. However, it has become evident that the correct functioning of an increasing number of genes on other chromosomes is required for testicular organogenesis. They include the SRY-related gene, SOX9, which plays important roles in both sex determination and chondrogenesis, as well as genes responsible for the production of growth factors, i.e. fibroblast growth factor 9, platelet derived growth factor A, and the members of the insulin-receptor family of genes. It is known, moreover, that differences between the sexes begin to develop long before the differentiation of Sertoli cells, including an increase in gonadal size and cell proliferation, and accelerated development of XY embryos at early pre-implantation stages. There is also evidence of transcription of Y-linked, and of X-linked, genes and of an enhanced metabolic rate in XY embryos. Furthermore, the condition of true hermaphroditism does not fit into a simple genotype/phenotype relationship. The proposal that “testis-determining” genes act by increasing metabolic rates rather than directly determining Sertoli cell differentiation can account for a number of observations that do not fit the current model, including pregonadal sex differences, the activity of the same gene in different organ systems, and the frequent co-existence of sexual and somatic abnormalities. It also sheds light on the pervasive differences between metabolic rates of mammalian males and females, while the facts of true hermaphroditism can be viewed as remnants of temperature-dependent sex determination in ectothermic vertebrates. Growing interest in mitochondria, which play a central role in the provision of energy to eukaryotic cells, makes a shift of paradigm from gonadal histology to energy metabolism timely, particularly since new techniques have become available for testing the hypothesis, and for widening the experimental approach to sex determination. If the hypothesis is correct, it would mean that male sex is determined by nuclear genes inherited from the father regulating the activity of maternally derived mitochondria.

Introduction

The genetics of sex determination is a child of the 20th century, which overturned the previously held view that sex was determined by the environment of the developing organism. Edmund Wilson, whose views underwent a radical change at the beginning of the new century, was himself one of the pioneers who brought about this change in outlook. His studies of the chromosomes of insects revealed two different dimorphisms in the spermatocytes: either a chromosome was present in one class and absent in the other, or both classes contained a chromosome of unequal size (Wilson, 1905). In the same year Netty Stevens (1905) found that in the common mealworm, Tenebrio molitor, males, but not females had one chromosome that was smaller than the others, and she concluded that “it seems certain that an egg fertilized by a spermatozoon which contains the small chromosome must produce a male, while one fertilized by a spermatozoon containing 10 chromosomes of equal size must produce a female”. The smaller chromosome became known as the “Y chromosome” and its partner as the “X chromosome” (Wilson, 1909), and both as “sex chromosomes” (Wilson, 1911).

During the third quarter of the 20th century, the sex chromosomes of the human and other mammalian species came to the fore, and during the last quarter of the century, there was a hunt for the mammalian sex-determining gene. It ended with the isolation of SRY from a 35 kb region of the human Y-chromosome (Sinclair et al., 1990), the cloning of a corresponding gene, named Sry, from the Y chromosome of the mouse (Gubbay et al., 1990), and the demonstration that Sry, when added as transgene to XX embryos, was able to induce male development in some of them (Koopman et al., 1991). The fact that some human XY females were found to have mutations in SRY was further evidence of the male-determining function of the gene (Affara et al., 1993).

However, the expectation that the identification of the gene would lead to an elucidation of a pathway of genes causing the “indifferent” gonadal rudiment to form a testis has not been fulfilled. The SRY gene encodes a DNA-binding protein, but no direct targets have been identified; hence, the mechanism by which it controls the development of the testis and the male phenotype remains essentially unknown. It may be appropriate, therefore, to examine the basis on which the present-day view of sex determination is built.

Section snippets

The current dogma

The current model of mammalian sex determination is based on three principles.

First, according to the embryological evidence, the gonads appear at first morphologically identical in both sexes and subsequently develop into ovaries or testes according to the sex chromosome constitution (van Wagenen and Simpson, 1965).

Second, the idea publicized by Alfred Jost (1953), that the difference between males and females begins with the histological differentiation of the hitherto undifferentiated gonad

When does sex differentiation begin?

Although the pivotal position of the differentiation of the fetal gonad into a testis capable of secreting hormones that masculinize the reproductive tract remains unchallenged, it has become evident that the differentiation of Sertoli cells is not the first phenotypic difference between XY and XX embryos. There are numerous findings suggesting that differences in the rate of development occur prior to the appearance of Sertoli cells and, indeed, the formation of genital ridges; and even though

True hermaphroditism, the environment and the control of metabolic rate

Unilateral manifestations in bilateral organs are of particular interest, because they suggest an environmental component in addition to the genetic causation (Mittwoch, 1996). True hermaphroditism is characterized by the presence of ovarian and testicular tissue in the same individual. The majority of patients have XX sex chromosomes, others have mixed cell lines with XX/XY and other combinations, and about 10% of patients are XY. Molecular analysis in most XX patients failed to detect

The “testis-determining” genes, SRY and SOX9

The role of SRY in testicular development remains unchallenged. However, the view that the activity of the gene is confined to the developing testis is less convincing. As shown by Clépet et al. (1993), SRY transcripts in humans are not confined to the presumptive and mature gonadal tissues in the embryo and adult, but are also found in a variety of other locations, including all fetal (16/17 weeks) tissues examined, i.e. adrenal, brain, liver, pancreas, small intestine, spleen, thymus and

Growth factors involved in the differentiation of the testis

There are at least a dozen genes known to play a role in the determination of sex (Lovell-Badge et al., 2002), and their number continues to grow. While the action of many of them is still unknown, they include some coding for known growth factors. One of them, Fgf9, codes for fibroblast growth factor 9, which is expressed in lung and other organs of mouse embryos (Colvin et al., 2001). Mice lacking fibroblast growth factor 9 due to a homozygous deletion of the gene die at birth, probably

Sex-determining genes: controllers of energy metabolism?

Differences between metabolic rates occur both within the same organism and between different organisms (Rolfe and Brown, 1997). The causes for such differences have not so far been clarified. Nevertheless, it seems reasonable to assume that for differences within an organism, nuclear genes that are differentially expressed in different organ systems are likely to be involved, whereas for differences between organisms different genotypes could be responsible in addition.

As regards

Hypothesis

I propose that a divergence in energy metabolism is at the root of the difference between the sexes. In mammals, males are metabolically more active than females from fertilization onwards, and this difference is amplified in the developing testes by the production of testicular hormones. The testis-determining genes, SRY and SOX9, effect an increase in metabolic rate in the tissues in which they are active, resulting in an increase of cell proliferation and of other developmental processes,

Testing the hypothesis

The present time is witnessing a rebirth in the study of mitochondria (Kiberstis, 1999; Rich, 2003), which has given rise to many new techniques for studying cellular metabolism. Since mitochondria produce most of the cell's energy by oxidative phosphorylation (Saraste, 1999), and since metabolically active cells tend to contain more mitochondria than less active ones, the question arises whether there is a difference in the number and activity of mitochondria in developing male and female

Conclusion

A shift in the paradigm of sex determination from gonadal histology to energy metabolism could account for a number of observations on normal and abnormal sexual development that do not fit into the current model. These include pregonadal sex differences, the interaction of genes and environment, the frequent co-existence of gonadal and somatic abnormalities, as well as sex biases in congenital anomalies (Lubinsky, 1997). The necessity to set the right metabolic rate also makes sense of the

Acknowledgments

I thank Ann Burgess for her comments on a draft manuscript, Peter Rich and David Wilkie for discussion, and the Wellcome Trust for a Research Expenses Grant in the History of Medicine.

References (73)

  • K.L. Betteridge

    Comparative aspects of conceptus growth

    Reproduction

    (2001)
  • K. Blaxter

    Energy Metabolism in Animals and Men

    (1989)
  • S.R. Blecher et al.

    Non-hormone-mediated sex chromosomal effects in developmentanother look at the Y chromosome-testicular hormone paradigm

  • F. Braña et al.

    Influence of incubation temperature on morphology, locomotor performance, and early growth of hatchling wall lizards (Podarcis muralis)

    J. Exp. Zool.

    (2000)
  • J. Brennan et al.

    Pdgfr-α mediates testis cord organization and fetal Leydig cell development in the fetal gonad

    Genes Dev.

    (2003)
  • M. Buehr et al.

    Mesonephric contribution to testis differentiation in the fetal mouse

    Development

    (1993)
  • P.S. Burgoyne et al.

    The genetic basis of XX-XY differences before sex differentiation in the mouse

    Philos. Trans. R. Soc. B

    (1995)
  • C. Clépet et al.

    The human SRY transcript

    Hum Mol. Genet.

    (1993)
  • M. Duchen et al.

    Imaging mitochondrial function in single cells

  • R.G. Edwards et al.

    Hypothesissex determination and germ cell formation are committed at the pronucleate stage in the mammalian embryo

    Mol. Hum. Reprod.

    (1999)
  • R.P. Erickson

    Does sex determination start at conception?

    BioEssays

    (1997)
  • M. Fiddler et al.

    A broader perspective of sexual differentiation

    Am. J. Med. Genet.

    (1997)
  • M. Fiddler et al.

    Expression of SRY transcripts in preimplantation human embryos

    Am. J. Med. Genet.

    (1995)
  • C.E. Ford

    Cytogenetics and sex determination in man and mammals

    J. Biosoc. Sci.

    (1970)
  • M. Fukuda et al.

    Right-sided ovulation favours pregnancies more than left-sided ovulations

    Hum. Genet.

    (2000)
  • J. Gubbay et al.

    A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes

    Nature

    (1990)
  • S. Hunt et al.

    Y-chromosomal and other factors in the development of testis size in mice

    Genet. Res.

    (1987)
  • A. Jost

    Problems of fetal endocrinologythe gonadal and hypophyseal hormones

    Rec. Progr, Horm. Res.

    (1953)
  • A. Jost et al.

    Early stages of testicular differentiation in the rat

    Hum. Genet.

    (1981)
  • P.A. Kiberstis

    Mitochondria make a comeback

    Science

    (1999)
  • P. Koopman

    Sry, Sox9 and mammalian sex determination

  • P. Koopman

    Gender benders

    Nature

    (2003)
  • P. Koopman et al.

    Male development of chromosomally female mice transgenic for Sry

    Nature

    (1991)
  • S.B.M. Kraak et al.

    A new hypothesis on the evolution of sex determination in vertebrates—big females ZW, big males XY

    Neth. J. Zool.

    (1993)
  • G. Krob et al.

    True hermaphroditismgeographical distribution, clinical findings, chromosomes and gonadal histology

    Eur. J. Pediat.

    (1994)
  • V.A. Lance

    Introduction: Environmental sex determination in reptilespatterns and processes

    J. Exp. Zool.

    (1994)
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