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Increased Transactivation Associated with SOX3 Polyalanine Tract Deletion in a Patient with Hypopituitarism

ALATZOGLOU, Kyriaki S.; KELBERMAN, Daniel; COWELL, Christopher T.; PALMER, Rodger; ARNHOLD, Ivo J. P.; MELO, Maria E.; SCHNABEL, Dirk; GRUETERS, Annette; DATTANI, Mehul T.
Fonte: ENDOCRINE SOC Publicador: ENDOCRINE SOC
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
28%
Backgound and Aims: Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability. Methods: We screened 154 patients with congenital hypopituitarism and an undescended posterior pituitary for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable septooptic dysplasia were screened for variability of the PA tract. Results: We report a novel 18-base pair deletion (p.A243_A248del6, del6PA) in a female patient with hypopituitarism resulting in a 2-fold increase in transcriptional activation in vitro, compared with wild-type SOX3. We also identified a previously reported seven-alanine expansion (p.A240_A241ins7, +7PA) in two male siblings with isolated GH deficiency and a distinct phenotype, in addition to the nonsynonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA...

Sox3 Is Required for Gonadal Function, but Not Sex Determination, in Males and Females

Weiss, Jeffrey; Meeks, Joshua J.; Hurley, Lisa; Raverot, Gerald; Frassetto, Andrea; Jameson, J. Larry
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2003 EN
Relevância na Pesquisa
28.05%
Sox3 is expressed in developing gonads and in the brain. Evolutionary evidence suggests that the X-chromosomal Sox3 gene may be the ancestral precursor of Sry, a sex-determining gene, and Sox3 has been proposed to play a role in sex determination. However, patients with mutations in SOX3 exhibit normal gonadal determination but are mentally retarded and have short stature secondary to growth hormone (GH) deficiency. We used Cre-LoxP targeted mutagenesis to delete Sox3 from mice. Null mice of both sexes had no overt behavioral deficits and exhibited normal GH gene expression. Low body weight was observed for some mice; overgrowth and misalignment of the front teeth was observed consistently. Female Sox3 null mice (−/−) developed ovaries but had excess follicular atresia, ovulation of defective oocytes, and severely reduced fertility. Pituitary (luteinizing hormone and follicle-stimulating hormone) and uterine functions were normal in females. Hemizygous male null mice (−/Y) developed testes but were hypogonadal. Testis weight was reduced by 42%, and there was extensive Sertoli cell vacuolization, loss of germ cells, reduced sperm counts, and disruption of the seminiferous tubules. We conclude that Sox3 is not required for gonadal determination but is important for normal oocyte development and male testis differentiation and gametogenesis.

Transcription Factor SOX3 Is Involved in X-Linked Mental Retardation with Growth Hormone Deficiency

Laumonnier, Frédéric; Ronce, Nathalie; Hamel, Ben C. J.; Thomas, Paul; Lespinasse, James; Raynaud, Martine; Paringaux, Christine; van Bokhoven, Hans; Kalscheuer, Vera; Fryns, Jean-Pierre; Chelly, Jamel; Moraine, Claude; Briault, Sylvain
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
28%
Physical mapping of the breakpoints of a pericentric inversion of the X chromosome (46,X,inv[X][p21q27]) in a female patient with mild mental retardation revealed localization of the Xp breakpoint in the IL1RAPL gene at Xp21.3 and the Xq breakpoint near the SOX3 gene (SRY [sex determining region Y]–box 3) (GenBank accession number NM_005634) at Xq26.3. Because carrier females with microdeletion in the IL1RAPL gene do not present any abnormal phenotype, we focused on the Xq breakpoint. However, we were unable to confirm the involvement of SOX3 in the mental retardation in this female patient. To validate SOX3 as an X-linked mental retardation (XLMR) gene, we performed mutation analyses in families with XLMR whose causative gene mapped to Xq26-q27. We show here that the SOX3 gene is involved in a large family in which affected individuals have mental retardation and growth hormone deficiency. The mutation results in an in-frame duplication of 33 bp encoding for 11 alanines in a polyalanine tract of the SOX3 gene. The expression pattern during neural and pituitary development suggests that dysfunction of the SOX3 protein caused by the polyalanine expansion might disturb transcription pathways and the regulation of genes involved in cellular processes and functions required for cognitive and pituitary development.

Over- and Underdosage of SOX3 Is Associated with Infundibular Hypoplasia and Hypopituitarism

Woods, Kathryn S.; Cundall, Maria; Turton, James; Rizotti, Karine; Mehta, Ameeta; Palmer, Rodger; Wong, Jacqueline; Chong, W. K.; Al-Zyoud, Mahmoud; El-Ali, Maryam; Otonkoski, Timo; Martinez-Barbera, Juan-Pedro; Thomas, Paul Q.; Robinson, Iain C.; Lovell-
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
28%
Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes...

Xenopus Sox3 activates sox2 and geminin and indirectly represses Xvent2 expression to induce neural progenitor formation at the expense of non-neural ectodermal derivatives

Rogers, Crystal D.; Harafuji, Naoe; Archer, Tenley; Cunningham, Doreen D.; Casey, Elena S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
28.17%
The SRY-related, HMG box SoxB1 transcription factors are highly homologous, evolutionarily conserved proteins that are expressed in neuroepithelial cells throughout neural development. SoxB1 genes are down-regulated as cells exit the cell-cycle to differentiate and are considered functionally redundant in maintaining neural precursor populations. However, little is known about Sox3 function and its mode of action during primary neurogenesis. Using gain and loss-of-function studies, we analyzed Sox3 function in detail in Xenopus early neural development and compared it to that of Sox2. Through these studies we identified the first targets of a SoxB1 protein during primary neurogenesis. Sox3 functions as an activator to induce expression of the early neural genes, sox2 and geminin in the absence of protein synthesis and to indirectly inhibit the Bmp target Xvent2. As a result, Sox3 increases cell proliferation, delays neurogenesis and inhibits epidermal and neural crest formation to expand the neural plate. Our studies indicate that Sox3 and 2 have many similar functions in this process including the ability to activate expression of geminin in naïve ectodermal explants. However, there are some differences; Sox3 activates the expression of sox2...

Identification of SOX3 as an XX male sex reversal gene in mice and humans

Sutton, Edwina; Hughes, James; White, Stefan; Sekido, Ryohei; Tan, Jacqueline; Arboleda, Valerie; Rogers, Nicholas; Knower, Kevin; Rowley, Lynn; Eyre, Helen; Rizzoti, Karine; McAninch, Dale; Goncalves, Joao; Slee, Jennie; Turbitt, Erin; Bruno, Damien; Ben
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
28.14%
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome–linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box–containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

A Systematic Survey and Characterization of Enhancers that Regulate Sox3 in Neuro-Sensory Development in Comparison with Sox2 Enhancers

Nishimura, Naoko; Kamimura, Yoshifumi; Ishida, Yoshiko; Takemoto, Tatsuya; Kondoh, Hisato; Uchikawa, Masanori
Fonte: MDPI Publicador: MDPI
Tipo: Artigo de Revista Científica
Publicado em 22/11/2012 EN
Relevância na Pesquisa
28.05%
Development of neural and sensory primordia at the early stages of embryogenesis depends on the activity of two B1 Sox transcription factors, Sox2 and Sox3. The embryonic expression patterns of the Sox2 and Sox3 genes are similar, yet they show gene-unique features. We screened for enhancers of the 231-kb genomic region encompassing Sox3 of chicken, and identified 13 new enhancers that showed activity in different domains of the neuro-sensory primordia. Combined with the three Sox3-proximal enhancers determined previously, at least 16 enhancers were involved in Sox3 regulation. Starting from the NP1 enhancer, more enhancers with different specificities are activated in sequence, resulting in complex overlapping patterns of enhancer activities. NP1 was activated in the caudal lateral epiblast adjacent to the posterior growing end of neural plate, and by the combined action of Wnt and Fgf signaling, similar to the Sox2 N1 enhancer involved in neural/mesodermal dichotomous cell lineage segregation. The Sox3 D5 enhancer and Sox2 N3 enhancer were also activated similarly in the diencephalon, optic vesicle and lens placode, suggesting analogies in their regulation. In general, however, the specificities of the enhancers were not identical between Sox3 and Sox2...

Cyclic AMP response element binding (CREB) protein acts as a positive regulator of SOX3 gene expression in NT2/D1 cells

Kovacevic-Grujicic, Natasa; Mojsin, Marija; Popovic, Jelena; Petrovic, Isidora; Topalovic, Vladanka; Stevanovic, Milena
Fonte: Korean Society for Biochemistry and Molecular Biology Publicador: Korean Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em /04/2014 EN
Relevância na Pesquisa
28.05%
SOX3 is one of the earliest neural markers in vertebrates, playing the role in specifying neuronal fate. In this study we have established first functional link between CREB and human SOX3 gene which both have important roles in the nervous system throughout development and in the adulthood. Here we demonstrate both in vitro and in vivo that CREB binds to CRE half-site located -195 to -191 within the human SOX3 promoter. Overexpression studies with CREB or its dominant-negative inhibitor A-CREB indicate that this transcription factor acts as a positive regulator of basal SOX3 gene expression in NT2/D1 cells. This is further confirmed by mutational analysis where mutation of CREB binding site results in reduction of SOX3 promoter activity. Our results point at CREB as a positive regulator of SOX3 gene transcription in NT2/D1 cells, while its contribution to RA induction of SOX3 promoter is not prominent. [BMB Reports 2014; 47(4): 197-202]

Identification of Highly Conserved Putative Developmental Enhancers Bound by SOX3 in Neural Progenitors Using ChIP-Seq

McAninch, Dale; Thomas, Paul
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 19/11/2014 EN
Relevância na Pesquisa
28.05%
The transcription factor SOX3 is expressed within most neural progenitor (NP) cells of the vertebrate central nervous system (CNS) and is essential for normal brain development in mice and humans. However, despite the widespread expression of Sox3, CNS defects in null mice are relatively mild due to functional redundancy with the other SOXB1 sub-group members Sox1 and Sox2. To further understand the molecular function of SOX3, we investigated the genome-wide binding profile of endogenous SOX3 in NP cells using ChIP-seq. SOX3 binding was identified at over 8,000 sites, most of which were intronic or intergeneic and were significantly associated with neurodevelopmental genes. The majority of binding sites were moderately or highly conserved (phastCons scores >0.1 and 0.5, respectively) and included the previously characterised, SOXB1-binding Nestin NP cell enhancer. Comparison of SOX3 and published ChIP-Seq data for the co-activator P300 in embryonic brain identified hundreds of highly conserved putative enhancer elements. In addition, we identified a subset of highly conserved putative enhancers for CNS development genes common to SOXB1 members in NP cells, all of which contained the SOX consensus motif (ACAAWR). Together these data implicate SOX3 in the direct regulation of hundreds of NP genes and provide molecular insight into the overlapping roles of SOXB1 proteins in CNS development.

Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3

Solomon, N.; Ross, S.; Morgan, T.; Belsky, J.; Hol, F.; Karnes, P.; Hopwood, N.; Myers, S.; Tan, A.; Warne, G.; Thomas, P.; Forrest, S.
Fonte: British Med Journal Publ Group Publicador: British Med Journal Publ Group
Tipo: Artigo de Revista Científica
Publicado em //2004 EN
Relevância na Pesquisa
37.83%
Introduction: Array comparative genomic hybridisation (array CGH) is a powerful method that detects alteration of gene copy number with greater resolution and efficiency than traditional methods. However, its ability to detect disease causing duplications in constitutional genomic DNA has not been shown. We developed an array CGH assay for X linked hypopituitarism, which is associated with duplication of Xq26–q27. Methods: We generated custom BAC/PAC arrays that spanned the 7.3 Mb critical region at Xq26.1–q27.3, and used them to search for duplications in three previously uncharacterised families with X linked hypopituitarism. Results: Validation experiments clearly identified Xq26–q27 duplications that we had previously mapped by fluorescence in situ hybridisation. Array CGH analysis of novel XH families identified three different Xq26–q27 duplications, which together refine the critical region to a 3.9 Mb interval at Xq27.2–q27.3. Expression analysis of six orthologous mouse genes from this region revealed that the transcription factor Sox3 is expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus. Discussion: Array CGH is a robust and sensitive method for identifying X chromosome duplications. The existence of different...

Polyalanine expansion mutations in the X-linked hypopituitarism gene SOX3 result in aggresome formation and impaired transactivation

Wong, J.; Farlie, P.; Holbert, S.; Lockhart, P.; Thomas, P.
Fonte: Frontiers in Bioscience Inc Publicador: Frontiers in Bioscience Inc
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
Relevância na Pesquisa
28.14%
Polyalanine expansion mutations have been identified in eight transcription factors that are associated with a range of congenital disorders. While some of these mutant proteins have been shown to generate cellular aggregates in heterologous cell lines, little is known about the mechanism by which these aggregates cause disease. Here we examine the aggregation and functional properties of the two known polyalanine expansion mutations associated with X-linked Hypopituitarism (XH), SOX3(22Ala) and SOX3(26Ala), which contain an additional seven and eleven alanine residues, respectively. SOX3(22Ala) and SOX3(26Ala) proteins form cytoplasmic aggregates and nuclear inclusions in transiently transfected COS-7 and CHO K1 cells, and in transfected explant cultures of chick neural epithelium. SOX3(26Ala) exhibits a more potent aggregation phenotype, resulting in significantly more cells with dispersed cytoplasmic and large perinuclear aggregates. SOX3(22Ala) and SOX3(26Ala) protein aggregates exhibit the key properties of aggresomes including vimentin redistribution, colocalisation with the Microtubule Organising Centre and sensitivity to microtubule disruption. This is the first time that aggresomes have been implicated in the aetiology of a polyalanine expansion disorder...

Sex determination in platypus and echidna: autosomal location of SOX3 confirms the absence of SRY from monotremes

Wallis, M.; Waters, P.; Delbridge, M.; Kirby, P.; Pask, A.; Grutzner, F.; Rens, W.; Ferguson-Smith, M.; Graves, J.
Fonte: Kluwer Academic Publ Publicador: Kluwer Academic Publ
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
Relevância na Pesquisa
37.83%
In eutherian (‘placental’) mammals, sex is determined by the presence or absence of the Y chromosome-borne gene SRY, which triggers testis determination. Marsupials also have a Y-borne SRY gene, implying that this mechanism is ancestral to therians, the SRY gene having diverged from its X-borne homologue SOX3 at least 180 million years ago. The rare exceptions have clearly lost and replaced the SRY mechanism recently. Other vertebrate classes have a variety of sex-determining mechanisms, but none shares the therian SRY-driven XX female:XY male system. In monotreme mammals (platypus and echidna), which branched from the therian lineage 210 million years ago, no orthologue of SRY has been found. In this study we show that its partner SOX3 is autosomal in platypus and echidna, mapping among human X chromosome orthologues to platypus chromosome 6, and to the homologous chromosome 16 in echidna. The autosomal localization of SOX3 in monotreme mammals, as well as non-mammal vertebrates, implies that SRY is absent in Prototheria and evolved later in the therian lineage 210–180 million years ago. Sex determination in platypus and echidna must therefore depend on another male-determining gene(s) on the Y chromosomes, or on the different dosage of a gene(s) on the X chromosomes.; M. C. Wallis...

Identification of SOX3 as an XX male sex reversal gene in mice and humans

Sutton, E.; Hughes, J.; White, S.; Sekido, R.; Tan, J.; Arboleda, V.; Rogers, N.; Knower, K.; Rowley, L.; Eyre, H.; Rizzoti, K.; McAninch, D.; Golcalves, J.; Slee, J.; Turbitt, E.; Bruno, D.; Bengtsson, H.; Harley, V.; Vilain, E.; Sinclair, A.; et al.
Fonte: Amer Soc Clinical Investigation Inc Publicador: Amer Soc Clinical Investigation Inc
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
28.14%
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.; Edwina Sutton...

Sox3 dosage regulation is important for roof plate specification during central nervous system development.

Lee, Kristie Pan Yu
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2011
Relevância na Pesquisa
38.35%
The central nervous system (CNS) is one of the most complicated organs in the body. Its development requires spatially and temporally dynamic but yet coordinated proliferation and differentiation of neural progenitors in order to allow the formation of the neural tube (NT) from a sheet-like neural plate, as well as the specification of different CNS domains from a homogeneous group of neural precursors. A number of genes have been identified to be important for the robust genetic and molecular regulation of the CNS development. One of these genes is SOX3, which encodes a SOX family transcription factor within a single exon. In humans, SOX3 duplications and mutations have been implicated in X-linked hypopituitarism (XH) with variable mental retardation, suggesting that CNS development is sensitive to SOX3 dosage. To recapitulate the condition in XH patients with SOX3 duplications, a transgenic Sox3 over-expression mouse model was generated in the Thomas laboratory. Two Sox3 transgenic lines were established. Intriguingly, they presented not with XH associated phenotypes, but with hallmarks of hydrocephalus. This thesis focuses on the characterisation of the hydrocephalus phenotype and the elucidation of the molecular pathogenesis that underlines the defect. Comprehensive morphological and expression analyses of single hemizygous and double hemizygous (mice with two transgene alleles...

Functional analysis of SOX3 binding at the Dbx1 locus.

Li, Pengcheng
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2014
Relevância na Pesquisa
38.25%
Sox3 a members of the SOX transcription factor family, is essential for normal brain development and required for growth of pituitary and hypothalamus. Sox3, as well as Sox2 which is another member in SOXB1 subfamily are widely expressed in neural progenitor cells and show functional redundancy. ChIP-seq data by Bergsland et al, 2011 has identified five putative SOX3 binding sites near/at the Dbx1 locus. Microarray data from the lab (N. Rogers, unpublished data) has identified Dbx1 as downregulated in Sox3 null neural progenitor cells. Together these data suggest that Dbx1 may be regulated directly by SOX3. To investigate the possibility that SOX3 regulates the Dbx1 locus in vitro, we performed gel shift assays and Luciferase Reporter Assays to see if SOX3 binds any of the five Dbx1 regulatory sites. Due to time constraints we were not able to optimize the gel shift assays to obtain any informative results. Secondly, we optimized Luciferase Reporter Assays providing preliminary data suggesting SOX3 may bind at one of the tested Dbx1 sites. To study the redundancy between Sox2 and Sox3, Sox2 was also tested in the Luciferase Reporter Assays indicating Sox2 may also regulate the same site as Sox3 . Due to time constraints, the other three binding sites remain to be analyzed in the future. The function of Dbx1 is best characterized in the context of the developing neural tube (also known as the spinal cord). To identify how other neural tube marker genes are regulated by Sox3...

Interchromosomal insertional translocation at Xq26.3 alters SOX3 expression in an individual with XX male sex reversal

Haines, B.; Hughes, J.; Corbett, M.; Shaw, M.; Innes, J.; Patel, L.; Gecz, J.; Clayton-Smith, J.; Thomas, P.
Fonte: Endocrine Society Publicador: Endocrine Society
Tipo: Artigo de Revista Científica
Publicado em //2015 EN
Relevância na Pesquisa
28.1%
CONTEXT: 46,XX male sex reversal occurs in approximately 1: 20 000 live births and is most commonly caused by interchromosomal translocations of the Y-linked sex-determining gene, SRY. Rearrangements of the closely related SOX3 gene on the X chromosome are also associated with 46,XX male sex reversal. It has been hypothesized that sex reversal in the latter is caused by ectopic expression of SOX3 in the developing urogenital ridge where it triggers male development by acting as an analog of SRY. However, altered regulation of SOX3 in individuals with XX male sex reversal has not been demonstrated. PATIENTS AND METHODS: Here we report a boy with SRY-negative XX male sex reversal who was diagnosed at birth with a small phallus, mixed gonads, and borderline-normal T. Molecular characterization of the affected individual was performed using array comparative genomic hybridization, fluorescent in situ hybridization of metaphase chromosomes, whole-genome sequencing, and RT-PCR expression analysis of lymphoblast cell lines. RESULTS: The affected male carries ∼774-kb insertion translocation from chromosome 1 into a human-specific palindromic sequence 82 kb distal to SOX3. Importantly, robust SOX3 expression was identified in cells derived from the affected individual but not from control XX or XY cells...

Expression and functional analysis of SOX3 in murine neurogenesis.

Rogers, Nicholas Alan
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2014
Relevância na Pesquisa
38.31%
The Sox (SRY-related HMG box) family of proteins are transcription factors. There are, in total, 30 different genes in the Sox family. Each Sox protein contains a HMG box (high-mobility-group) which functions as a DNA binding domain. The HMG box is highly conserved (>50% identity) throughout the entire Sox family. Sox3 belongs to the SoxB1 subgroup. SOX3 has been associated with human CNS related disorders. Duplication and mutations of SOX3 have been identified in patients with X-linked hypopituitarism (XH). Afflicted XH patients suffer from varying levels of mental retardation and pituitary hormone deficiencies which can lead to short stature. Previous studies have shown that Sox3 is expressed in nascent neuroprogenitor cells and is functionally required in mammals for development of the dorsal telencephalon and hypothalamus. Using a SOX3-specific antibody, data within my thesis shows that murine SOX3 expression is maintained throughout telencephalic neurogenesis and is restricted to progenitor cells with neuroepithelial and radial glial morphologies. In addition, characterisation of SOX3 expression within the adult neurogenic regions indicates that it is a lifelong marker of neuroprogenitor cells. In contrast to the telencephalon...

Identification of SOX3 as an XX male sex reversal gene in mice and humans

Sutton, Edwina; Hughes, James; White, Stefan; Sekido, Ryohei; Tan, Jacqueline; Arboleda, Valerie; Rogers, Nicholas; Knower, Kevin; Rowley, Lynn; Eyre, Helen; Rizzoti, Karine; McAninch, Dale; Gonçalves, João; Slee, Jennie; Turbitt, Erin; Bruno, Damien; B
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Publicado em /01/2011 ENG
Relevância na Pesquisa
38.17%
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

Identification of highly conserved putative developmental enhancers bound by SOX3 in neural progenitors using ChIP-Seq

McAninch, D.; Thomas, P.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
28.05%
The transcription factor SOX3 is expressed within most neural progenitor (NP) cells of the vertebrate central nervous system (CNS) and is essential for normal brain development in mice and humans. However, despite the widespread expression of Sox3, CNS defects in null mice are relatively mild due to functional redundancy with the other SOXB1 sub-group members Sox1 and Sox2. To further understand the molecular function of SOX3, we investigated the genome-wide binding profile of endogenous SOX3 in NP cells using ChIP-seq. SOX3 binding was identified at over 8,000 sites, most of which were intronic or intergeneic and were significantly associated with neurodevelopmental genes. The majority of binding sites were moderately or highly conserved (phastCons scores .0.1 and 0.5, respectively) and included the previously characterised, SOXB1-binding Nestin NP cell enhancer. Comparison of SOX3 and published ChIP-Seq data for the co-activator P300 in embryonic brain identified hundreds of highly conserved putative enhancer elements. In addition, we identified a subset of highly conserved putative enhancers for CNS development genes common to SOXB1 members in NP cells, all of which contained the SOX consensus motif (ACAAWR). Together these data implicate SOX3 in the direct regulation of hundreds of NP genes and provide molecular insight into the overlapping roles of SOXB1 proteins in CNS development.; Dale McAninch...

SOX3 expression in the glial system of the developing and adult mouse cerebellum

Cheah, P.S.; Thomas, P.Q.
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
Publicado em //2015 EN
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BACKGROUND: The cerebellum plays a vital role in equilibrium, motor control, and motor learning. The discrete neural and glial fates of cerebellar cells are determined by the molecular specifications (e.g. transcription factors) of neuroprogenitor cells that are influenced by local microenvironment signals. In this study, we evaluated the expression and function of Sox3, a single-exon gene located on the X chromosome, in the developing cerebellum. RESULT: In the embryonic and early postnatal cerebellum, SOX3-positive-cells were detected in the ventricular zone, indicating that SOX3 expression is present in a subset of the cerebellar precursor cell population. In the young adult cerebellum, this expression was diminished in cerebellar cells, suggesting its limited role in cerebellar progenitors. SOX3-positive-cells were also found in the cerebellar mantle zone. Further immunohistochemistry analyses revealed that SOX3 was not expressed in Purkinje neurons. Using glial markers in the early postnatal cerebellum, we found that virtually all of the SOX3-positive-cells were glial cells, although not all glial cells were SOX3-positive-cells. We also determined the impact of transgenic expression using a loss-of-function (Sox3 null) model. We did not observe any developmental defects in the cerebellum of the Sox3 null mice. CONCLUSIONS: Our results indicate that the SOX3 protein is not expressed in cerebellar neurons and is instead expressed exclusively in the cerebellar glial system in a subset of mature glial cells. Although the expression of Sox3 cerebellar glial development is lineage-restricted...