[Paleopsych] SW: On Female Development

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Medical Biology: On Female Development

    The following points are made by Ieuan A. Hughes (New Engl. J. Med.
    2004 351:748):
    1) It is an indisputable fact that the constitutive sex in mammalian
    fetal development is female. Furthermore, a functioning ovary is not
    required for the female phenotype, whereas a testis is mandatory for
    male development. More than 50 years after Jost performed experiments
    in rabbit embryos in which castration was followed by testis
    engraftment, his observations remain a beacon of clarity illuminating
    the mechanism of fetal sexual differentiation -- the physical
    phenotype consistent with male or female sex.(1)
    2) Another indisputable fact of mammalian fetal sexual development is
    the morphogenesis of a bipotential gonad in the genital ridge, dual
    internal genital ducts, and a common anlagen for the external
    genitalia. So what factors determine sexual dimorphism? Clearly, the
    production of an XY zygote at fertilization is the simplest
    explanation for the development of a bipotential gonad into a testis.
    The production of müllerian inhibiting substance by Sertoli cells and
    androgens by Leydig cells in a critical-concentration-dependent and
    time-dependent manner induces male sexual differentiation by means of
    a hormone-dependent process.
    3) In contrast, a panoply of genes are involved in gonadal development
    and, hence, sex determination.(2) There is compelling evidence that a
    gene on the short arm of the Y chromosome close to the
    pseudo-autosomal region -- called SRY, for the sex-determining region
    of the Y chromosome -- is the key player in testis development. The
    translocation of SRY to the X chromosome during paternal meiosis
    explains testis development in 90 percent of XX males. Mutations in
    SRY are present in 10 to 15 percent of XY females who have complete
    gonadal dysgenesis, and the insertion of the corresponding mouse gene
    sry into XX mouse embryos results in male offspring.
    4) A number of other genes are involved in testis determination, such
    as SOX9, which is induced by SRY; steroidogenic factor 1 (SF1); Wilms'
    tumor 1 (WT1); and DAX1. Perturbations in the structure or function of
    these genes or their products cause sex-disorder syndromes in humans.
    More testis-determining genes have been identified through studies in
    transgenic mice. However, their relevance to disorders such as XY
    gonadal dysgenesis in humans remains unknown.
    5) Are there no key genes for human ovarian determination and
    differentiation of the female reproductive tract? Some syndromes
    associated with gene duplication cause XY sex reversal. For instance,
    the duplication of a 160-kb region on the short arm of the X
    chromosome (Xp21.3) leads to the development of an XY female. Since
    this dose-sensitive sex locus contains the DAX1 gene, one might ask
    whether DAX1 is an ovarian-determining gene. Apparently not, since
    female mice with a mutant dax1 gene have normal ovaries. Studies of
    dax1 in concert with sry in transgenic mice suggest that DAX1 normally
    complements the role of SRY in testis determination but can act in an
    antitestis manner when it is overexpressed. A factor whose role in
    female sexual development seems more critical is highlighted by the
    duplication of chromosome 1p31-p35. Within this region lies the WNT4
    gene, which encodes one member of a large family of locally acting
    growth factors that are involved in intracellular signaling.(3) The
    overexpression of WNT4 up-regulates DAX1 and may cause sex reversal by
    means of the same mechanism to which Xp21 duplication is ascribed.(4)
    References (abridged):
    1. Jost A. Problems of fetal endocrinology: the gonadal and
    hypophyseal hormones. Recent Prog Horm Res 1953;8:379-418
    2. MacLaughlin DT, Donahoe PK. Sex determination and differentiation.
    N Engl J Med 2004;350:367-378
    3. Dale TC. Signal transduction by the Wnt family of ligands. Biochem
    J 1998;329:209-223
    4. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female
    development in mammals is regulated by Wnt-4 signalling. Nature
    New Engl. J. Med. http://www.nejm.org
    Related Material:
    American Scientist 2003 91:218
    The following points are made by John G. Vandenbergh:
    1) X and Y chromosomes are only the beginning of sex determination.
    Biologists have recently taken a closer look at the events between
    fertilization and sexual maturity that establish an individual's
    sexual characteristics. These events help explain variability among
    individuals in sexual anatomy, physiology and behavior. For example,
    an XX individual can exhibit some masculine traits if hormone
    production or sensitivity is abnormal during early development.
    2) In fact, there is almost a continuum of sexual traits between male
    and female. The ability of environmental influences during development
    to produce such a continuum demonstrates that another classical
    dichotomy, between nature and nurture, is in fact a synergy: Genes and
    environment work together to produce an organism. Specific genes are
    only turned on when the environment of the cell, tissue, organ or
    organism calls for them. In the case of sexual characteristics, one
    mechanism by which environmental variables exert their influence is
    through the activity of hormones.
    3) Hormones are substances released by cells into the bloodstream,
    where they travel throughout the body and influence the function of
    other, distant cells. Hormone molecules themselves, or the enzymes
    that produce those molecules, are encoded by the genome, but hormone
    concentrations can be modulated by a wide array of environmental
    factors, including stress, food consumption, temperature, and time of
    year. In turn, hormone concentrations modulate the expression of genes
    in a variety of different cell and tissue types, producing anatomical,
    physiological and behavioral differences.
    Related Material:
    The following points are made by Huntington F. Willard (Nature 2003
    1) Because of its distinctive role in sex determination, the Y
    chromosome has long attracted special attention from geneticists,
    evolutionary biologists and even the lay public. It is known to
    consist of regions of DNA that show quite distinctive genetic behavior
    and genomic characteristics. The two human sex chromosomes, X and Y,
    originated a few hundred million years ago from the same ancestral
    "autosome" -- a non-sex chromosome --during the evolution of sex
    determination. They then diverged in sequence over the succeeding
    aeons. Nowadays, there are relatively short regions at either end of
    the Y chromosome that are still identical to the corresponding regions
    of the X chromosome, reflecting the frequent exchange of DNA between
    these regions ("recombination") that occurs during sperm production.
    But more than 95% of the modern-day Y chromosome is male-specific,
    consisting of some 23 million base pairs (Mb) of euchromatin -- the
    part of our genome containing most of the genes -- and a variable
    amount of heterochromatin, consisting of highly repetitive DNA and
    often dismissed as non-functional. In an accomplishment that can only
    be described as heroic, Skaletsky et al (Nature 2003 423:825) have
    reported the complete sequence of the 23-Mb euchromatic segment, which
    they designate the MSY, for "male-specific region of the Y".
    2) Prioritization in the Human Genome Project had led to the
    heterochromatic regions of the Y and other chromosomes being set aside
    to be dealt with later, if ever. But there was reason to hope that the
    euchromatin of the Y chromosome would present no more difficult a
    sequencing challenge than that found elsewhere in the genome. That
    supposition could not have been more wrong. As Skaletsky et al report,
    the MSY is a mosaic of complex and interrelated sequences that made
    this one of the most problematic regions of the human genome thus far
    to be successfully sequenced and assembled.
    3) For instance, approximately 10 to 15% of the MSY consists of
    stretches of sequence that moved there from the X chromosome within
    only the past few million years. These stretches are still 99%
    identical to their X-chromosome counterparts and are dominated by a
    high proportion of interspersed repetitive sequences, with only two
    genes. A further 20% of the MSY consists of a class of sequences
    ("X-degenerate" sequences) that are more distantly related to the X
    chromosome, reflecting their more ancient common origin. And the
    remainder comprises a web of Y-specific repetitive sequences that make
    up a series of palindromes -- sequences that read the same on both
    strands of the DNA double helix, with two "arms" stretching out from a
    central point of mirrored symmetry. These palindromes come in a range
    of sizes, up to almost 3 Mb in length, with more than 99.9% identity
    between the two arms of each palindrome.
    Nature http://www.nature.com/nature
    Related Material:
    The following points are made by Bob Beale (The Scientist 2001 23
    1) The understanding of sex is currently experiencing important
    changes due to new insights gained from sociology, biology, and
    medicine. The differences between females and males, once believed
    clearcut, now appear blurred. For example, there is now evidence that
    the Y chromosome has degenerated over evolutionary time. In mice, some
    genes involved in early stages of sperm production are on the female X
    chromosome. In addition, the gene that can produce ambiguous genitalia
    has been identified.
    2) Genetic studies are revealing that men and women are more similar
    than distinct. Of the approximately 31,000 genes in the human genome,
    men and women differ only in the two sex chromosomes, X and Y, and
    only a few dozen genes are apparently involved. Moreover, it is now
    known that the Y chromosome has only approximately 30 genes, and many
    of those are involved in basic housekeeping duties or in regulating
    sperm production. In contrast, the X chromosome has hundreds of genes
    with a vast array of roles.
    3) Strong evidence exists that the X and Y chromosomes were once a
    matching pair of X chromosomes. It is unclear why the male sex
    chromosome, the Y chromosome, shrunk and shed most of its genes over
    time. Humans are not alone in this phenomenon: the degeneration of the
    Y chromosome is well documented in fruit flies and is clearly an
    ongoing process in all animals. Detailed molecular and embryological
    studies are revealing how genes determine the anatomical sex of a
    fetus and how the process can be corrupted.
    The Scientist http://www.the-scientist.com

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