Expression and subcellular localization of SF-1, SOX9, WT1, and AMH proteins during early human testicular development

Barbara, Pascal de Santa; Moniot, Brigitte; Poulat, Françis; Berta, Philippe

doi:10.1002/(sici)1097-0177(200003)217:3<293::aid-dvdy7>3.0.co;2-p

Cited by 158 publications

(86 citation statements)

References 28 publications

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“…The two NLSs of the SOX9 HMG box (12), drive the exclusively nuclear localization of SOX9 in COS-7 cells. However, SOX9 is also cytoplasmic in NIH 3T3-transfected cells and together with previous in vivo observations (11), this let us hypothesize that SOX9 could bear a NES allowing its nucleo-cytoplasmic shuttling. The presence of a NES sequence was further suggested by the nuclear accumulation of SOX9 in transfected NIH 3T3 cells incubated in the presence of the export inhibitor, LMB.…”

Section: Discussionsupporting

confidence: 68%

“…The dynamic subcellular redistribution of SOX9 protein at the time of sexual differentiation was reported in mouse and human gonads (7,11). However, the regulation of this process and its relevance to sex determination had not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Immunofluorescence studies on mouse and human XX and XY embryo gonad sections revealed that cytoplasmic SOX9 protein is present in undifferentiated gonads of both sexes, but that in the male gonad it becomes nuclear at the onset of testis differentiation (7,11). These results, together with the previous identification of two nuclear localization signal (NLS) sequences in the HMG box (12), let us to hypothesize that SOX9 is able to shuttle between the nucleus and the cytoplasm and thus may contain a nuclear export signal (NES).…”

mentioning

confidence: 99%

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A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination

Gasca

Cañizares

Barbara³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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127

125

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In mammals, male sex determination starts when the Y chromosome Sry gene is expressed within the undetermined male gonad. One of the earliest effect of Sry expression is to induce upregulation of Sox9 gene expression in the developing gonad. SOX9, like SRY, contains a high mobility group domain and is sufficient to induce testis differentiation in transgenic XX mice. Before sexual differentiation, SOX9 protein is initially found in the cytoplasm of undifferentiated gonads from both sexes. At the time of testis differentiation and anti-Mü llerian hormone expression, it becomes localized to the nuclear compartment in males whereas it is down-regulated in females. In this report, we used NIH 3T3 cells as a model to examine the regulation of SOX9 nucleo-cytoplasmic shuttling. SOX9-transfected cells expressed nuclear and cytoplasmic SOX9 whereas transfected cells treated with the nuclear export inhibitor leptomycin B, displayed an exclusive nuclear localization of SOX9. By using SOX9 deletion constructs in green fluorescent protein fusion proteins, we identified a functional nuclear export signal sequence between amino acids 134 and 147 of SOX9 high mobility group box. More strikingly, we show that inhibiting nuclear export with leptomycin B in mouse XX gonads cultured in vitro induced a sex reversal phenotype characterized by nuclear SOX9 and anti-Mü llerian hormone expression. These results indicate that SOX9 nuclear export signal is essential for SOX9 sexspecific subcellular localization and could be part of a regulatory switch repressing (in females) or triggering (in males) male-specific sexual differentiation. E xpression of Sry (1, 2) in the undetermined male gonad induces a variety of morphogenetic events including cell proliferation, cell migration, Sertoli cell fate determination, and subsequent sex cord formation (3-6). The earliest downstream effect of Sry may be up-regulation of Sox9 expression in the developing gonad (7), although it has yet to be shown at the molecular level. SOX9 is related to SRY by its high mobility group (HMG) domain. Interestingly, SOX9 is better conserved during evolution and, like SRY, is sufficient to induce testis differentiation in female transgenic mice (8). Furthermore, heterozygous mutations in SOX9 lead to campomelic dysplasia, a skeletal malformation syndrome associated with sex reversal in 75% of XY patients (9, 10).Immunofluorescence studies on mouse and human XX and XY embryo gonad sections revealed that cytoplasmic SOX9 protein is present in undifferentiated gonads of both sexes, but that in the male gonad it becomes nuclear at the onset of testis differentiation (7, 11). These results, together with the previous identification of two nuclear localization signal (NLS) sequences in the HMG box (12), let us to hypothesize that SOX9 is able to shuttle between the nucleus and the cytoplasm and thus may contain a nuclear export signal (NES). Prototypic NESs are short hydrophobic sequences rich in leucine residues (13-16) regulating the subcellular localization of several ...

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination

Gasca

Cañizares

Barbara³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

127

125

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“…Although the current study investigated only transcript abundance, examining the subcellular localization of the SOX9 protein might explain its continued gene expression. As is the case in both mouse and human, SOX9 may be localized to the nucleus of preSertoli cells in the testis, exerting transcriptional control over downstream genes, whereas in ovarian cells remaining cytoplasmic and, thus, inactive as a transcription factor (de Santa Barbara et al, 2000;Lasala et al, 2004). Future work should investigate whether a similar nuclear-cytoplasmic shuttling system is important in TSD.…”

Section: Exploring Functional Roles Of Genes In a Nonmodel Systemmentioning

confidence: 91%

Expression of Sox9, Mis, and Dmrt1 in the gonad of a species with temperature‐dependent sex determination

Shoemaker

Ramsey

Queen

et al. 2007

Developmental Dynamics

128

103

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Sex determination in vertebrates, the process of forming an ovary or testis from a bipotential gonad, can be initiated by genetic or environmental factors. Elements of the downstream molecular pathways underlying these different sex-determining mechanisms have been evolutionarily conserved. We find the first evidence that Sox9 expression is preferentially organized in the testis early in the temperature-sensitive period in a species with temperature-dependent sex determination (Trachemys scripta). This pattern occurs before sexually dimorphic Mis expression and in a temporal hierarchy that is similar to mammals. Furthermore, we extend previous findings that Dmrt1 expression at early stages of sex determination has a dimorphic pattern consistent with a possible upstream role in determining the fate of the bipotential gonad.

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“…A proteí-na WT1 é capaz de ativar a transcrição do gene SRY in vitro (26), havendo evidências de que atue sinergicamente com a proteína SRY ativando promotores contendo sítios de ligação para esta última (44). Por outro lado, estudos in vitro indicam que WT1 e outros fatores de regulação de transcrição podem de forma cooperativa ativar a transcrição do gene AMH (AntiMüllerian Hormone) (45,46), uma vez que após a diferenciação testicular o WT-1 continua sendo transcrito nas células de Sertoli do testículo fetal. No entanto, sua expressão não é limitada ao testículo: no ovário fetal, é detectada nas células epiteliais e na camada granulosa; no rim fetal, se expressa no mesênquima, na vesícula renal e nos podócitos em desenvolvimento.…”

Section: Biologia Molecular Da Determinação Do Sexounclassified

Genes envolvidos na determinação e diferenciação do sexo

Mello

Assumpção

Hackel

2005

Arq Bras Endocrinol Metab

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RESUMOO sexo cromossômico é estabelecido na fertilização pela presença de um cromossomo X ou Y. O desenvolvimento dos sexos masculino e feminino passa, num primeiro momento, pela especialização das gônadas em testículos ou ovários; os demais processos decorrem de efeitos secundários provocados pelos hormônios por elas produzidos. As etapas de determinação e diferenciação das gônadas em testícu-los ou em ovários e a diferenciação dos genitais externos masculinos ou femininos envolvem a expressão específica de uma cascata de genes. Esses genes, seus respectivos padrões de expressão, bem como seus envolvimentos na manifestação de patologias ligadas ao desenvolvimento gonadal e dos genitais externos serão abordados nesta revisão. ABSTRACT Genes Involved in Sex Determination and Differentiation.Chromosomal sex is established at fertilization by the presence of an X or Y chromosome. The first step of male and female development is gonadal specialization in testes or ovaries; all other processes that follow result from secondary effects produced by testis and ovary hormones. Gonadal determination and differentiation and the development of external genitalia involve time-and tissue-specific expression of genes forming a gene cascade. Those genes, their expression profile and their role in the pathological manifestations related to gonadal and external genitalia development will be discussed in this review. (Arq Bras Endocrinol Metab 2005;49/1:14-25 ) Keywords: Chromosome; Gene; Gonadal differentiation; Gonadal dysgenesis; Sex; SRY N OS SERES HUMANOS E NA MAIORIA DOS MAMÍFEROS, os processos de determinação e diferenciação sexuais estão intrinsecamente associados à presença ou à ausência do cromossomo Y no cariótipo (1,2). O evento pivô na determinação sexual é a especialização das gônadas; as demais diferenças entre os sexos são efeitos secundários devidos aos hormônios por elas produzidos (3). O processo como um todo é classicamente dividido em quatro etapas: a determinação do sexo cromossômico, que é estabelecida na fertilização; a diferenciação das gônadas em testículos ou em ovários; a diferenciação dos genitais internos e externos masculinos ou femininos a partir de estruturas indiferenciadas presentes no embrião, que é dependente da presença ou ausência de testículos; e a diferenciação sexual secundária, que é a resposta de vários tecidos aos hormônios produzidos pelas gônadas para completar o fenótipo sexual. Portanto, a expressão revisão

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Expression and subcellular localization of SF-1, SOX9, WT1, and AMH proteins during early human testicular development

Cited by 158 publications

References 28 publications

A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination

A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination

Expression of Sox9, Mis, and Dmrt1 in the gonad of a species with temperature‐dependent sex determination

Genes envolvidos na determinação e diferenciação do sexo

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