Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds

Silva, Sara Morais da; Hacker, Adam; Harley, Vincent R.; Goodfellow, Peter N.; Swain, Amanda; Lovell-Badge, Robin

doi:10.1038/ng0996-62

Cited by 723 publications

(200 citation statements)

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“…The expression of Sox9 at high levels in Sertoli cells also favors the hypothesis that additional proteins are needed to differentiate the phenotype of chondrocytes from that of Sertoli cells (20,21). Hence, the purpose of the present study was to further identify sequences in the Col2a1 48-bp enhancer essential for its chondrocyte-specific activity and to determine whether chondrocyte-specific nuclear proteins bound to these sequences.…”

mentioning

confidence: 78%

“…In situ hybridization during mouse embryogenesis showed that Sox9 is expressed in all chondroprogenitor cells; Sox9 expression generally parallels that of Col2a1 even in some non-chondrocytic cells and increases together with that of Col2a1 when frank chondrocyte differentiation takes place (5,18,19). The expression of Sox9 in gonadal ridges and later in the Sertoli cells of the testis presumably accounts for the sex reversal in CD patients (20,21). Overall, the abnormal skeletal manifestations of CD patients and the pattern of expression of Sox9 during embryonic development suggest that Sox9 plays an important role in the pathway of chondrocyte differentiation.…”

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confidence: 99%

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Three High Mobility Group-like Sequences within a 48-Base Pair Enhancer of the Col2a1 Gene Are Required for Cartilage-specific Expression in Vivo

Zhou¹,

Lefebvre²,

Zhang

et al. 1998

Journal of Biological Chemistry

162

159

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To understand the molecular mechanisms by which mesenchymal cells differentiate into chondrocytes, we have used the gene for an early and abundant marker of chondrocytes, the mouse pro-␣1(II) collagen gene (Col2a1), to delineate a minimal sequence needed for chondrocyte-specific expression and to identify the DNA-binding proteins that mediate its activity. We show here that a 48-base pair (bp) Col2a1 intron 1 sequence specifically targets the activity of a heterologous promoter to chondrocytes in transgenic mice. Mutagenesis studies of this 48-bp element identified three separate sites (sites 1-3) that were essential for its chondrocytespecific enhancer activity in both transgenic mice and transient transfections. Mutations in sites 1 and 2 also severely inhibited the chondrocyte-specific enhancer activity of a 468-bp Col2a1 intron 1 sequence in vivo. SOX9, an SRY-related high mobility group (HMG) domain transcription factor, was previously shown to bind site 3, to bend the 48-bp DNA at this site, and to strongly activate this 48-bp enhancer as well as larger Col2a1 enhancer elements. All three sites correspond to imperfect binding sites for HMG domain proteins and appear to be involved in the formation of a large chondrocytespecific complex between the 48-bp element, Sox9, and other protein(s). Indeed, mutations in each of the three HMG-like sites of the 48-bp element, which abolished chondrocyte-specific expression of reporter genes in transgenic mice and in transiently transfected cells, inhibited formation of this complex. Overall our results suggest a model whereby both Sox9 and these other proteins bind to several HMG-like sites in the Col2a1 gene to cooperatively control its expression in cartilage.Acquisition of the chondrocytic phenotype occurs along a major pathway of differentiation of mesenchymal cells (1, 2). With the goal of identifying transcription factors that control chondrocyte-specific gene expression, we used the gene for collagen type II (Col2a1), 1 an early and abundant marker of chondrocytes (3-5), to delineate minimal sequences in this gene that control chondrocyte-specific expression in transgenic mice. Elucidation of the transcriptional mechanisms that control the chondrocyte-specific expression of the Col2a1 gene should provide important insights into the molecular specifications of chondrocytes.We previously identified a 48-bp element in intron 1 of the mouse Col2a1 gene that, when present as four tandem copies, conferred chondrocyte-specific expression both in transgenic mice and in transient expression experiments in tissue culture cells (6). A multimerized 18-bp element located at the 3Ј end of the 48-bp sequence also acted as a powerful chondrocyte-specific enhancer in transient transfection assays of rat chondrosarcoma (RCS) cells and mouse primary chondrocytes but not of fibroblasts (6).SOX9 is a member of a family of transcription factors with a DNA-binding domain that shows more than 50% similarity with the high mobility group HMG DNA-binding domain of SRY, the testis-determi...

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confidence: 78%

mentioning

confidence: 99%

Three High Mobility Group-like Sequences within a 48-Base Pair Enhancer of the Col2a1 Gene Are Required for Cartilage-specific Expression in Vivo

Zhou¹,

Lefebvre²,

Zhang

et al. 1998

Journal of Biological Chemistry

162

159

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“…3). Sex reversal was not observed in the AMH-NICD1 model, because the levels of Sox9, 84,85 Dax1, 86 and Foxl2 87 expression in Sertoli cells were not significantly altered in our microarray (GSE37073).…”

Section: Phenotype Of Sertoli Cells In Wild-type and Amh-nicd1 Testesmentioning

confidence: 99%

NOTCH signaling in Sertoli cells regulates gonocyte fate

Garcia

Hofmann

2013

Cell Cycle

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“…These include SOX9, a highly conserved HMG domain transcription factor that is implicated in testis development across all groups from fish to reptiles, birds and mammals (Morais da Silva et al 1996. In female embryos of egg-laying species such as birds and reptiles, estrogen is required for proper ovary formation, and testis-enriched DMRT1 can antagonise estrogen production (Elbrecht & Smith 1992, Yao et al 2004, Lambeth et al 2014.…”

Section: Sex Determination and Testis Development In Non-mammalian Vementioning

confidence: 99%

The role of non-coding RNAs in male sex determination and differentiation

2015

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A complex network of gene regulation and interaction drives male sex determination and differentiation. While many important proteincoding genes that are necessary for proper male development have been identified, many disorders in human sex development are still unexplained at the molecular level. This suggests that key factors and regulatory mechanisms are still unknown. In recent years, extensive data have shown that different classes of non-coding RNAs (ncRNAs) play a role in almost all developmental and physiological pathways.Here we review what is known about their role in male sex determination and differentiation not only in mammals, but also other species. While for some processes a key role for ncRNA has been identified, we are still far from having a complete picture.Reproduction (2015) 150 R93-R107

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Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds

Cited by 723 publications

References 53 publications

Three High Mobility Group-like Sequences within a 48-Base Pair Enhancer of the Col2a1 Gene Are Required for Cartilage-specific Expression in Vivo

Three High Mobility Group-like Sequences within a 48-Base Pair Enhancer of the Col2a1 Gene Are Required for Cartilage-specific Expression in Vivo

NOTCH signaling in Sertoli cells regulates gonocyte fate

The role of non-coding RNAs in male sex determination and differentiation

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