Comparative gene expression analysis of genital tubercle development reveals a putative appendicular Wnt7 network for the epidermal differentiation

Institute for Molecular Bioscience, The University of Queensland, St. Lucia 4072, Australia.
Developmental Biology (Impact Factor: 3.55). 08/2010; 344(2):1071-87. DOI: 10.1016/j.ydbio.2010.05.495
Source: PubMed


Here we describe the first detailed catalog of gene expression in the developing lower urinary tract (LUT), including epithelial and mesenchymal portions of the developing bladder, urogenital sinus, urethra, and genital tubercle (GT) at E13 and E14. Top compartment-specific genes implicated by the microarray data were validated using whole-mount in situ hybridization (ISH) over the entire LUT. To demonstrate the potential of this resource to implicate developmentally critical features, we focused on gene expression patterns and pathways in the sexually indeterminate, androgen-independent GT. GT expression patterns reinforced the proposed similarities between development of GT, limb, and craniofacial prominences. Comparison of spatial expression patterns predicted a network of Wnt7a-associated GT-enriched epithelial genes, including Gjb2, Dsc3, Krt5, and Sostdc1. Known from other contexts, these genes are associated with normal epidermal differentiation, with disruptions in Dsc3 and Gjb2 showing palmo-plantar keratoderma in the limb. We propose that this gene network contributes to normal foreskin, scrotum, and labial development. As several of these genes are known to be regulated by, or contain cis elements responsive to retinoic acid, estrogen, or androgen, this implicates this pathway in the later androgen-dependent development of the GT.

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    • "Recent studies suggest Wnt7A may play an important role in regulating epithelial cell differentiation in mice. Expression of Wnt7A is tightly co-regulated with epithelial genes during genital tubercle development [18], and in uterine Wnt7A is specifically expressed in epithelial cells [19], [20]. "
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    ABSTRACT: Until now the essential transcription factor that determines the epithelial phenotype of breast cancer has not been identified and its role in epithelial-to-mesenchymal transition (EMT) and tumor progression remain unclear. Here, by analyzing large expression profiles of human breast cancer cells, we found an extraordinary correlation between the expression of Grainyhead transcription factor Grhl2 and epithelial marker E-cadherin. Knockdown of Grhl2 expression by shRNA in human mammary epithelial cell MCF10A leads to down-regulation of E-cadherin and EMT. Grhl2 is down-regulated in disseminated cancer cells that have undergone EMT, and over-expression of Grhl2 is sufficient to induce epithelial gene expression. Large clinical datasets reveal that expression of Grhl2 is significantly associated with poor relapse free survival and increased risk of metastasis in breast cancer patients. In mouse models, over-expression of Grhl2 significantly promotes tumor growth and metastasis. Further testing of several Grhl2 regulated genes leads to the same conclusions that the tumorigenic and metastatic potentials of tumor cells are linked to epithelial phenotype but not mesenchymal phenotype. In conclusion, our findings indicate that Grhl2 plays an essential role in the determination of epithelial phenotype of breast cancers, EMT and tumor progression.
    PLoS ONE 12/2012; 7(12):e50781. DOI:10.1371/journal.pone.0050781 · 3.23 Impact Factor
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    • "(Brunskill et al., 2008; Thiagarajan et al., 2011), the identification of previously unidentified subcompartments (Chiu et al., 2010; Georgas et al., 2009; Mugford et al., 2009) and the association between gene networks and key developmental processes (Brunskill et al., 2008; Chiu et al., 2010). It has also been referred to, or utilised by, a number of other studies investigating gene expression and development (Combes et al., 2009; Dallosso et al., 2009; Gerber et al., 2009; Parreira et al., 2009; Shah et al., 2010; Surendran et al., 2010). "
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    ABSTRACT: The GenitoUrinary Development Molecular Anatomy Project (GUDMAP) is an international consortium working to generate gene expression data and transgenic mice. GUDMAP includes data from large-scale in situ hybridisation screens (wholemount and section) and microarray gene expression data of microdissected, laser-captured and FACS-sorted components of the developing mouse genitourinary (GU) system. These expression data are annotated using a high-resolution anatomy ontology specific to the developing murine GU system. GUDMAP data are freely accessible at via easy-to-use interfaces. This curated, high-resolution dataset serves as a powerful resource for biologists, clinicians and bioinformaticians interested in the developing urogenital system. This paper gives examples of how the data have been used to address problems in developmental biology and provides a primer for those wishing to use the database in their own research.
    Development 07/2011; 138(13):2845-53. DOI:10.1242/dev.063594 · 6.46 Impact Factor
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    • "It is essential, therefore, to investigate the mechanisms underlying the teratogenic effects of RA during GT development. Many growth factor signaling pathways have been reported to be involved in GT embryonic development, including Sonic hedgehog (Shh) (Haraguchi et al., 2001; Seifert et al., 2009a) and Bone morphogenetic protein (Bmp) signaling pathways (Suzuki et al., 2003; Chiu et al., 2010). During organogenesis, RA signaling regulates Shh signaling during brain development, caudal body trunk formation, and prostate budding (Ribes et al., 2006; Vezina et al., 2008; Ribes et al., 2009). "
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    ABSTRACT: Retinoic acid (RA) plays pivotal roles in organogenesis, and both excessive and reduced amounts of RA cause developmental abnormalities. Reproductive organs are susceptible to teratogen toxigenicity, and the genital tubercle (GT) is one such representative organ. The physiological function of endogenous RA signaling and the mechanisms of RA-induced teratogenicity are poorly understood during the GT development. The objective of this study is to understand the developmental and teratogenic roles of RA during GT development by analyzing genetically modified mouse models. We found dynamic patterns of gene expression for the RA-synthesizing enzyme, Raldh2, and for the RA-catabolizing enzyme, Cyp26b1, during GT development. Rarb, an indicator gene for RA signaling, starts its expression in the prospective corpus cavernosum penis and in the urethral plate epithelium (UE), which plays central roles during GT development. Excessive RA signaling in Cyp26b1(-/-) mutants leads to abnormal extents of cell proliferation and differentiation during GT development, and also upregulates expression of growth factor signalings. They include Sonic hedgehog (Shh) signaling and Bone morphogenetic protein (Bmp) signaling, which are expressed in the UE and its bilateral mesenchyme. RA signaling positively regulatesShh and Bmp4 expression during GT development as testified also by the experiment of RA administration and analyses of loss-of-function of RA signaling mutants. Thus, RA signaling is involved in the developmental cascade necessary for UE formation and GT development. Birth Defects Res (Part B) XX:1-10, 2011.  ©2011 Wiley Periodicals, Inc.
    Birth Defects Research Part B Developmental and Reproductive Toxicology 01/2011; 95(1). DOI:10.1002/bdrb.20344 · 0.77 Impact Factor
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