Determination and stability of sex

Ottolenghi, Chris; Uda, Manuela; Crisponi, Laura; Omari, Shakib; Cao, Antonio; Forabosco, Antonino; Schlessinger, David

doi:10.1002/bies.20515

Cited by 49 publications

(52 citation statements)

References 71 publications

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“…This is compatible with the phenotype of mouse mutants in which there is no colonization of the gonad by germ cells. This leads to gonads blocked in an apparently undifferentiated state ( [31] and references therein). Moreover, recall that absence or dysfunction of SRY in an XY background generally leads to a streak gonad or to an impaired ovary, [13,32] which argues for the existence of autonomous signal(s) in the somatic cells but also of signals resulting from a dialog with the gonocytes that would help in the making of a functional ovary.…”

Section: Foxl2: a Molecular Actor In The Spotlightmentioning

confidence: 99%

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Veitia

2010

BioEssays

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Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male-specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male-specific genes during development, postnatally and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions. Keywords:.F OXL2; ovary determination; ovarian maintenance IntroductionGonadal sex determination is a process that implies a unique decision to make a testis or an ovary out of a bipotential primordium. In most mammals, sex determination is equated with testis determination, whereas ovarian determination has been considered a default process. That is, absence of the testisdetermining factor would automatically lead to the development of an ovary (in appropriate conditions). Recent articles challenge this view and show that in the ovary active mechanisms are required to maintain the differentiated state. [1,2] The bipotential gonad is made up of four presumptive cell lineages: germ cells (which have an extraembryonic origin) and three types of somatic cells. The somatic component involves the supporting cell precursors, which will give rise to Sertoli cells in the male or granulosa cells in the female, the steroidogenic precursors, which differentiate into Leydig cells (male) and theca cells (female), and finally the connective tissue cells yielding other important structures. [3] From a genetic perspective, the SRY gene is pivotal in switching on the testis-determining cascade.[4] Indeed, murine Sry transcripts appear in the presumptive Sertoli cells from 10.5 days postcoitum and for about 2 days, at the right moment for testis determination. [5] In other mammals, including man, SRY is expressed from the period of testis determination until adulthood [6]). It seems now that the main task of Sry/SRY is to directly activate the gene Sox9, which also encodes a transcription factor. Recently a gonad-specific enhancer that mediates testis Sox9 expression, called TESCO, has been identified. [7] Indeed, Sry along with the steroidogenic factor 1 (Sf1) binds to multiple elements within the TESCO. Moreover, mutation, co-transfection, and sex-reversal studies suggest the existence of a positive feedback circuit. First, Sf1 and Sry cooperatively up-regulate Sox9 transcription. Then, Sox9 and Sf1 recognize the enhancer to maintain the expression of the former in the absence of Sr...

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Section: Foxl2: a Molecular Actor In The Spotlightmentioning

confidence: 99%

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Veitia

2010

BioEssays

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“…It requires the activation of a number of genes, including FOXL2 and WNT4. Double knockout mice for these two genes result in testis development in spite of a XX sex chromosomal constitution (Ottolenghi et al, 2007). These insights into normal sex determination must be kept in mind when searching for explanations for the various forms of DSD (see below).…”

Section: Normal Male Versus Female Developmentmentioning

confidence: 99%

New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD)

Hersmus

Leeuw

Wolffenbuttel

et al. 2008

Molecular and Cellular Endocrinology

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“…Conversely, varying levels of differentiation of Sertoli or Leydig cells are reported in XX sexreversal. With the exception of genetic mutants [3,37,38], SOX9 expression is rarely detected. The expression of only SOX9 was reported previously in mouse ovaries transplanted under renal capsules [39].…”

Section: Discussionmentioning

confidence: 99%

Evidence for Almost Complete Sex-reversal in Bovine Freemartin Gonads: Formation of Seminiferous Tubule-like Structures and Transdifferentiation into Typical Testicular Cell Types

Harikae

Tsunekawa

Hiramatsu

et al. 2012

Journal of Reproduction and Development

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Abstract. During mammalian sex determination of XY fetuses, SRY induces SOX9 in Sertoli cells, resulting in formation of testes with seminiferous tubules, interstitial Leydig cells and peritubular myoid cells. Meanwhile XX fetuses without SRY develop ovaries. In cattle, most XX heifers born with a male twin, so-called freemartins, develop nonfunctioning ovaries and genitalia with an intersex phenotype. Interestingly, freemartins sometimes develop highly masculinized gonads with seminiferous tubule-like structures despite the absence of SRY. However, in these cases, the degree of masculinization in each gonadal somatic cell type is unclear. Here, we report a rare case of a freemartin Japanese black calf with almost complete XX sexreversal. Gross anatomical analysis of this calf revealed the presence of a pair of small testis-like gonads with rudimentary epididymides, in addition to highly masculinized genitalia including a pampiniform plexus, scrotum and vesicular gland. Histological and immunohistochemical analyses of these masculinized gonads revealed well-defined seminiferous tubulelike structures throughout the whole gonadal parenchyma. In epithelia of these tubules, SOX9-positive supporting cells (i.e., Sertoli cells) were found to be arranged regularly along the bases of tubules, and they were also positive for GDNF, one of the major factors for spermatogenesis. 3β-HSD-positive cells (i.e., Leydig cells) and SMA-positive peritubular myoid cells were also identified around tubules. Therefore, for the first time, we found the transdifferentiation of ovarian somatic cells into all testicular somatic cell types in the XX freemartin gonads. These data strongly support the idea of a high sexual plasticity in the ovarian somatic cells of mammalian gonads.

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Determination and stability of sex

Cited by 49 publications

References 71 publications

FOXL2 versus SOX9: A lifelong “battle of the sexes”

FOXL2 versus SOX9: A lifelong “battle of the sexes”

New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD)

Evidence for Almost Complete Sex-reversal in Bovine Freemartin Gonads: Formation of Seminiferous Tubule-like Structures and Transdifferentiation into Typical Testicular Cell Types

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