Campomelic Dysplasia with XY Sex Reversal: Diverse Phenotypes Resulting from Mutations in a Single Genea

Schafer, Alan J.; Foster, Jamie W.; Kwok, Cheni; Weller, P A; Guioli, Silvana; Goodfellow, Peter N.

doi:10.1111/j.1749-6632.1996.tb56252.x

Cited by 39 publications

(23 citation statements)

References 41 publications

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“…The pattern of SOX9 expression in mice could explain, in part, the phenotype found in some patients with campomelic dysplasia. These individuals are usually developmentally delayed and up to one third have been described to have developmental abnormalities of the kidney (Schafer et al, 1996). The identification of SOX9 mRNA and protein in mammary tissue, suggest that SOX9 may play a role in mammary development, growth, or physiology.…”

Section: Discussionmentioning

confidence: 99%

RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition

et al. 2002

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Retinoic acid receptors (RARs) are ligand-dependent transcription factors which are members of the steroid/ thyroid hormone receptor gene family. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. PCR-amplified subtractive hybridization was used to identify candidate retinoidregulated genes that may be involved in growth inhibition. One candidate gene identified was SOX9, a member of the high mobility group (HMG) box gene family of transcription factors. SOX9 gene expression is rapidly stimulated by RAR-agonists in T-47D cells and other retinoidinhibited breast cancer cell lines. In support of this finding, a database search indicates that SOX9 is expressed as an EST in breast tumor cells. SOX9 is known to be expressed in chondrocytes where it regulates the transcription of type II collagen and in testes where it plays a role in male sexual differentiation. RAR pan-agonists and the RARa-selective agonist Am580, but not RXR agonists, stimulate the expression of SOX9 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not stimulate SOX9 in breast cancer cell lines which were not growth inhibited by retinoids. Expression of SOX9 in T-47D cells leads to cycle changes similar to those found with RARagonists while expression of a dominant negative form of SOX9 blocks RA-mediated cell cycle changes, suggesting a role for SOX9 in retinoid-mediated growth inhibition.

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Section: Discussionmentioning

confidence: 99%

RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition

et al. 2002

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“…Loss of function mutations of the SRY gene account for approximately 10 to 15% of the cases. In addition, mutations in SOX9, SF1, and at least twelve other loci have been implicated in XY sex reversal [Schafer et al, 1996;Achermann et al, 1999;Fleming and Vilain, 2005]. XX sex reversal is less common, and the majority of cases (80 to 85%) are caused by a translocation of SRY to another chromosomes.…”

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confidence: 99%

Genetics of Ovarian Differentiation: <i>Rspo1</i>, a Major Player

Chassot

Gregoire

Magliano

et al. 2008

Sex Dev

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In mammals, the sex of the embryo is determined during development by its commitment either to the male or female genetic program regulating testicular or ovarian organogenesis. Major steps towards unraveling sex determination in mammals are achieved by the identification of key genes involved in human pathologies and the application of mouse genetics to analyze their function. While the expression of Sry and Sox9 is sufficient to induce the male devel- opmental program, the molecular pathways that specify ovarian differentiation were unclear before the recent demonstration that mutations in the RSPO1 gene induce female-to-male sex reversal in XX patients. By generating the corresponding mouse model, we have shown that Rspo1 is so far the earliest known gene controlling the female genetic developmental program. Rspo1 activates the canonical β-catenin signaling pathway required for female somatic cell differentiation and germ cell commitment into meiosis. The aim of this review is to describe the roles of R-spondins (Rspo)in developmental processes and disorders and the current knowledge obtained from murine models. A particular focus will be on Rspo1 and its crucial function in sex determination.

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“…Cartilage, another mesenchymalderived cell lineage, is a highly specialized connective tissue that is important for skeletal development (de Crombrugghe et al 2001;Shum and Nuckolls 2002). The transcription factor Sox9 is required for cartilage development (Bi et al 1999;Panda et al 2001), and loss of Sox9 causes campomelic dysplasia, a dominant skeletal disease (Foster 1996;Schafer et al 1996). Sox9 expression has been shown to be down-regulated by cytokines such as TNF␣ and IL-1 (Murakami et al 2000), which may explain the deleterious role of inflammatory cytokines in diseases such as rheumatoid arthritis and osteoporosis (Fujita et al 1990;Chen and Goeddel 2002).…”

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confidence: 99%

NF-κB mediates inhibition of mesenchymal cell differentiation through a posttranscriptional gene silencing mechanism

Sitcheran¹,

Cogswell²,

Baldwin³

2003

Genes Dev.

112

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Cytokines, such as tumor necrosis factor-␣ (TNF␣), potently inhibit the differentiation of mesenchymal cells and down-regulate the expression of Sox9 and MyoD, transcription factors required for chondrocyte and myocyte development. Previously, we demonstrated that NF-B controls TNF␣-mediated suppression of myogenesis through a mechanism involving MyoD mRNA downregulation. Here, we show that NF-B also suppresses chondrogenesis and destabilizes Sox9 mRNA levels. Multiple copies of an mRNA cis-regulatory motif (5-ACUACAG-3) are necessary and sufficient for NF-Bmediated Sox9 and MyoD down-regulation. Thus, in response to cytokine signaling, NF-B modulates the differentiation of mesenchymal-derived cell lineages via RNA sequence-dependent, posttranscriptional downregulation of key developmental regulators. Received May 19, 2003; revised version accepted July 24, 2003. In multicellular organisms, control of proliferation, differentiation, and apoptosis is essential for survival. Defects in cell differentiation can lead to aberrations in other cellular processes, resulting in diseases such as cancer (Scott 1997). Mesenchymal progenitor cells give rise to the skeletal cells, including myocytes, chondrocytes, osteoblasts, and adipocytes (Pittenger et al. 1999;Caplan and Bruder 2001). Notably, cytokines such as tumor necrosis factor-␣ (TNF␣) can inhibit the differentiation of mesenchymal stem cells (Filipak et al. 1988;Gilbert et al. 2000) and suppress the expression of genes important for their differentiation (Guttridge et al. 2000;Murakami et al. 2000;Gilbert et al. 2002;Ruan et al. 2002). However, the molecular mechanism underlying this suppression is not known.Nuclear factor B (NF-B) complexes are dimeric, sequence-specific transcription factors that regulate the expression of a large number of genes in response to a variety of cellular conditions, including infection and in- . Generally, NF-B is described as a transcriptional activator, and there is ample data demonstrating that NF-B positively regulates transcription. However, there is also some evidence that NF-B can repress transcription. For example, the p50 NF-B subunit, which binds DNA but lacks transcriptional activation domains, may inhibit the transcription of certain genes through interaction with transcriptional corepressors such as HDAC-1 (Zhong et al. 2002).Recently, we demonstrated that NF-B can inhibit the differentiation of mesenchymally derived skeletal muscle cells (Guttridge et al. 2000). TNF␣-mediated activation of NF-B in C2C12 myoblasts led to a dramatic decrease in endogenous MyoD mRNA levels. Expression of the p65 subunit of NF-B induced the loss of coexpressed MyoD message, and a fragment of the MyoDcoding sequence fused to a heterologous gene conferred NF-B-dependent loss of that chimeric mRNA. These data suggested that the mechanism underlying MyoD mRNA down-regulation and inhibition of muscle-cell differentiation involves a unique posttranscriptional silencing mechanism. Cartilage, another mesenchymalderived cell lineage, is a highly ...

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Campomelic Dysplasia with XY Sex Reversal: Diverse Phenotypes Resulting from Mutations in a Single Genea

Cited by 39 publications

References 41 publications

RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition

RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition

Genetics of Ovarian Differentiation: <i>Rspo1</i>, a Major Player

NF-κB mediates inhibition of mesenchymal cell differentiation through a posttranscriptional gene silencing mechanism

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