Fine Mapping Suggests that the Goat <i>Polled Intersex Syndrome</i> and the Human <i>Blepharophimosis Ptosis Epicanthus Syndrome</i> Map to a 100-kb Homologous Region

Schibler, Laurent; Cribiu, Edmond; Oustry-Vaiman, Anne; Furet, Jean-Pierre; Vaiman, Daniel

doi:10.1101/gr.10.3.311

Cited by 49 publications

(29 citation statements)

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“…Fine-mapping studies suggested that both PIS (on 1q43) and the human blepharophimosis ptosis epicanthus syndrome (BPES) (on 3q23) loci mapped to a 100-kb homologous region. [15] The PIS mutation has been characterized and involves a small deletion (probably removing regulatory elements) that leads to a misregulation of several genes in the region. [16] More or less at the same time, mutations in the gene FOXL2 were shown to be responsible for BPES.…”

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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“…The mapping has subsequently been refined and, by haplotype analysis, the mutation localized to one BAC (376H9, Fig. 3) which has been partially sequenced (Vaiman et al, 1999;Schibler et al, 2000). By sequence comparison between horned (PIS +/+ ) and sex-reversed (PIS -/-) animal DNAs, the mutation was found to be an 11.7-kb deletion encompassing no known coding sequences (Pailhoux et al, 2001b).…”

Section: Quest For the Pis Mutationmentioning

confidence: 99%

“…Once the PIS mutation had been limited to one BAC (Schibler et al, 2000), different strategies were developed in order to isolate putative transcribed regions in this DNA fragment. Out of the 20 putative exons tested, only PISRT1 has shown a dimorphic expression pattern in the gonads with higher levels in the ovaries compared to testes during fetal life (Pailhoux et al, 2001b).…”

Section: Pis Is a Transcriptional Regulatory Regionmentioning

confidence: 99%

Expression studies of the PIS-regulated genes suggest different mechanisms of sex determination within mammals

Pannetier

Servel

Cocquet

et al. 2003

Cytogenet Genome Res

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In mammals, the Y-located SRY gene is known to induce testis formation from the indifferent gonad. A related gene, SOX9, also plays a critical role in testis differentiation in mammals, in birds and reptiles. It is now assumed that SRY acts upstream of SOX9 in the sex determination cascade, but the regulatory link which should exist between these two genes remains unknown. Studies on XX sex reversal in polled goats (PIS mutation: Polled Intersex Syndrome) have led to the discovery of a female-specific locus crucial for ovarian differentiation. This genomic region is composed of at least two genes, FOXL2 and PISRT1, which share a common transcriptional regulatory region, PIS. In this review, we present the expression pattern of these PIS-regulated genes in mice. The FOXL2 expression profile of mice is similar to that described in goats in accordance with a conserved role of this ovarian differentiating gene in mammals. On the contrary, the PISRT1 expression profile is different between mice and goats, suggesting different mechanisms of the primary switch in the testis determination process within mammals. A model based on two different modes of SOX9 regulation in mice and other mammals is proposed in order to integrate our results into the current scheme of gonad differentiation.

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“…Furthermore, a strong linkage disequilibrium among unrelated animals was detected with the two central markers of this region, suggesting a probable location for PIS in a ∼100 kb DNA region contained in one BAC (376H9). High resolution comparative mapping with human data shows that this DNA segment is the homologue of the human region associated with Blepharophimosis Ptosis Epicanthus inversus Syndrome, BPES [12]. This finding suggests that a homologous gene(s) could be responsible for the pathologies observed in humans and goats.…”

Section: Linkage Analysis Of the Pis Mutationmentioning

confidence: 81%

Positional cloning of the PIS mutation in goats and its impact on understanding mammalian sex-differentiation

Pailhoux¹,

Vigier²,

Schibler

et al. 2005

Genet. Sel. Evol.

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-In goats, the PIS (polled intersex syndrome) mutation is responsible for both the absence of horns in males and females and sex-reversal affecting exclusively XX individuals. The mode of inheritance is dominant for the polled trait and recessive for sex-reversal. In XX PIS −/− mutants, the expression of testis-specific genes is observed very precociously during gonad development. Nevertheless, a delay of 4-5 days is observed in comparison with normal testis differentiation in XY males. By positional cloning, we demonstrate that the PIS mutation is an 11.7-kb regulatory-deletion affecting the expression of two genes, PISRT1 and FOXL2 which could act synergistically to promote ovarian differentiation. The transcriptional extinction of these two genes leads, very early, to testis-formation in XX homozygous PIS −/− mutants. According to their expression profiles and bibliographic data, we propose that FOXL2 may be an ovary-differentiating gene, and the non-coding RNA PISRT1, an anti-testis factor repressing SOX9, a key regulator of testis differentiation. Under this hypothesis, SRY, the testis-determining factor would inhibit these two genes in the gonads of XY males, to ensure testis differentiation. PIS mutation / goat / gonad differentiation / XX sex-reversal / ovary development

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Fine Mapping Suggests that the Goat Polled Intersex Syndrome and the Human Blepharophimosis Ptosis Epicanthus Syndrome Map to a 100-kb Homologous Region

Cited by 49 publications

References 25 publications

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

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

Expression studies of the PIS-regulated genes suggest different mechanisms of sex determination within mammals

Positional cloning of the PIS mutation in goats and its impact on understanding mammalian sex-differentiation

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