- Email: [email protected]
Analysis of ovarian signalling pathways in the postgenomic era
RBMOnline - Vol 6. No 1. 13–14 Reproductive BioMedicine Online; www.rbmonline.com/Article/752 on web 30 October 2002
Symposium: Genetic aspects of follicular and oocyte growth Guest Editor: Aaron JW Hsueh
Analysis of ovarian signalling pathways in the postgenomic era Aaron Hsueh, Professor of Reproductive Biology at Stanford University, has contributed to the field of ovarian physiology by investigating the gonadotrophin and growth factor actions in the ovary and molecular biology of gonadotrophin receptors. His group also studied the role of oocyte-derived GDF-9 in follicle development and identified ovarian Bcl-2 genes during follicle atresia. The Hsueh lab launched the Ovarian Kaleidoscope database (www.ovary.stanford.edu) to document ovarian genes. They also pioneered the use of bioinformatic approaches to discover novel polypeptide hormones and receptors, including glycoprotein hormone subunits A2B5 (thyrostimulin) and multiple leucine-rich repeatcontaining, G protein-coupled receptors (LGR). Two LGR were recently found as relaxin receptors. AJW Hsueh Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94305–5317, USA Correspondence: e-mail: [email protected] Ovarian functions are regulated by diverse endocrine and paracrine factors acting on granulosa, thecal, luteal, oocyte, and other cell types. In addition to circulating gonadotrophins, a large number of paracrine factors are secreted in the ovary and act on neighbouring cells through unique signalling pathways. Recent advances in genome projects for human and several model organisms revealed the nucleotide (and deduced amino acid) sequences of the entire repertoire of genes from diverse organisms, thus providing an unprecedented opportunity to study genes important for hormone-based ligand signalling (Leo et al., 2002). It is becoming clear that there are only a limited number of genes in the genomic ‘toolkit’ and the function of proteins is usually accomplished by interactions with other proteins. Gene products in a given cell are expressed in a concerted manner and canonical signalling pathways are conserved in different cell types of diverse organisms. In mammalian cells, multiple paralogous genes are derived as the result of whole genome duplications during early chordate evolution as well as the duplication of individual genes. The resulting genes with high sequence homology could serve similar, and sometimes modified, functions in the canonical pathways operating in different organs. Although tissue-specific expression of paralogous genes is unique, key genes in a particular canonical signalling pathway are always present in a given cell type. Recently developed DNA microarray analyses allow simultaneous detection of the transcripts for thousands of genes including all paralogous genes in different pathways. Using this approach, tissue-specific paralogues in selected signalling pathways can be easily identified. Elucidation of the tissue-specific expression of key players in a given signalling pathway allowed the identification of paralogous genes functioning in individual tissues. For analysing ovarian gene expression and function, we have set up the Ovarian Kaleidoscope database (OKdb)
(http://ovary.stanford.edu/) that provides information regarding the biological function, expression pattern, and regulation of genes expressed in the ovary (Ben-Shlomo et al., 2002). With the increasing number of genes that can be probed simultaneously using DNA microarrays, the GenMapp project (http://www.genmapp.org) has focused on the construction and analysis of gene pathway maps based on known canonical signalling pathways. This tool provides analogous graphic representation of the relative expression of selected groups of genes categorized by their known positions in physiological pathways. Based on this approach, the OKdb offers a gene map for the analyses of ovarian ‘bottleneck’ genes, the deletion of which is associated with infertility. Using a similar approach, different ovarian-specific intracellular signalling pathways also can be elucidated. This ovarian ‘mini’-symposium deals with intracellular signalling pathways activated by ovarian paracrine factors and associated changes in the normal and abnormal demise of ovarian cells. LaPlot and his colleagues (LaPolt et al., 2003) described the role of cyclic GMP, which is downstream of natriuretic peptide receptors, nitric oxides, and guanylyl cyclases, in the modulation of ovarian functions. Recent advances in ovarian physiology indicate that past emphasis on the hormonal regulation of the growth and differentiation of ovarian cells neglected an important aspect of ovarian physiology, namely ovarian cell apoptosis. The article by (Vaskivuo and Tapanainen, 2003) summarizes ‘normal’ death (or apoptosis) of ovarian cells during development and the role of hormonal systems in the regulation of apoptosis signalling pathways important in the regulation of follicle atresia. Finally, Ben-Shlomo, (Ben-Shlomo, 2003) proposed the use of intracellular signalling pathway analyses to elucidate the molecular basis of a pathological condition in the ovary. He discussed the role of genes in the insulin signalling pathway associated with polycystic ovarian syndrome (PCOS). This
13
Symposium - Analysis of ovarian signalling pathways - AJW Hsueh
article emphasizes the importance of the analysis of differential usage and potential abnormality of genes in the insulin signalling pathway in peripheral and ovarian tissues of patients with PCOS. With recent advances in genomics, one can anticipate the identification of ovarian paralogous genes in diverse signalling pathways, together with the high throughput analysis of ovarian gene expression pattern in normal and diseased ovaries. The eventual integration of physiological and pathological data in different ovarian cell types will allow rapid advances in ovarian genomics and the elucidation of molecular defects leading to ovarian diseases such as polycystic ovarian syndrome and premature ovarian failure. These advances could also allow improved treatment of human infertility associated with ovarian dysfunctions.
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References Ben-Shlomo I, Vitt UA, Hsueh AJW 2002 Perspective: the ovarian kaleidoscope database-II. Functional genomic analysis of an organ-specific database. Endocrinology 143, 2041–2044. Ben-Shlomo I 2003 The polycystic ovary syndrome: What insulin resistance got to do with it? Reproductive BioMedicine Online 6, 36–42 – this issue. LaPolt PS, Leung K, Ishimaru R et al. 2003 Roles of cyclic GMP in modulating ovarian functions. Reproductive BioMedicine Online 6, 15–23 – this issue. Leo CP, Hsu SY, Hsueh AJW 2002 Hormonal genomics. Endocrine Reviews 23, 369–381. Vaskivuo TE, Tapanainen JS 2003 Apoptosis in the human ovary. Reproductive BioMedicine Online 6, 24–35– this issue.
Symposium: Genetic aspects of follicular and oocyte growth Guest Editor: Aaron JW Hsueh
Analysis of ovarian signalling pathways in the postgenomic era Aaron Hsueh, Professor of Reproductive Biology at Stanford University, has contributed to the field of ovarian physiology by investigating the gonadotrophin and growth factor actions in the ovary and molecular biology of gonadotrophin receptors. His group also studied the role of oocyte-derived GDF-9 in follicle development and identified ovarian Bcl-2 genes during follicle atresia. The Hsueh lab launched the Ovarian Kaleidoscope database (www.ovary.stanford.edu) to document ovarian genes. They also pioneered the use of bioinformatic approaches to discover novel polypeptide hormones and receptors, including glycoprotein hormone subunits A2B5 (thyrostimulin) and multiple leucine-rich repeatcontaining, G protein-coupled receptors (LGR). Two LGR were recently found as relaxin receptors. AJW Hsueh Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94305–5317, USA Correspondence: e-mail: [email protected] Ovarian functions are regulated by diverse endocrine and paracrine factors acting on granulosa, thecal, luteal, oocyte, and other cell types. In addition to circulating gonadotrophins, a large number of paracrine factors are secreted in the ovary and act on neighbouring cells through unique signalling pathways. Recent advances in genome projects for human and several model organisms revealed the nucleotide (and deduced amino acid) sequences of the entire repertoire of genes from diverse organisms, thus providing an unprecedented opportunity to study genes important for hormone-based ligand signalling (Leo et al., 2002). It is becoming clear that there are only a limited number of genes in the genomic ‘toolkit’ and the function of proteins is usually accomplished by interactions with other proteins. Gene products in a given cell are expressed in a concerted manner and canonical signalling pathways are conserved in different cell types of diverse organisms. In mammalian cells, multiple paralogous genes are derived as the result of whole genome duplications during early chordate evolution as well as the duplication of individual genes. The resulting genes with high sequence homology could serve similar, and sometimes modified, functions in the canonical pathways operating in different organs. Although tissue-specific expression of paralogous genes is unique, key genes in a particular canonical signalling pathway are always present in a given cell type. Recently developed DNA microarray analyses allow simultaneous detection of the transcripts for thousands of genes including all paralogous genes in different pathways. Using this approach, tissue-specific paralogues in selected signalling pathways can be easily identified. Elucidation of the tissue-specific expression of key players in a given signalling pathway allowed the identification of paralogous genes functioning in individual tissues. For analysing ovarian gene expression and function, we have set up the Ovarian Kaleidoscope database (OKdb)
(http://ovary.stanford.edu/) that provides information regarding the biological function, expression pattern, and regulation of genes expressed in the ovary (Ben-Shlomo et al., 2002). With the increasing number of genes that can be probed simultaneously using DNA microarrays, the GenMapp project (http://www.genmapp.org) has focused on the construction and analysis of gene pathway maps based on known canonical signalling pathways. This tool provides analogous graphic representation of the relative expression of selected groups of genes categorized by their known positions in physiological pathways. Based on this approach, the OKdb offers a gene map for the analyses of ovarian ‘bottleneck’ genes, the deletion of which is associated with infertility. Using a similar approach, different ovarian-specific intracellular signalling pathways also can be elucidated. This ovarian ‘mini’-symposium deals with intracellular signalling pathways activated by ovarian paracrine factors and associated changes in the normal and abnormal demise of ovarian cells. LaPlot and his colleagues (LaPolt et al., 2003) described the role of cyclic GMP, which is downstream of natriuretic peptide receptors, nitric oxides, and guanylyl cyclases, in the modulation of ovarian functions. Recent advances in ovarian physiology indicate that past emphasis on the hormonal regulation of the growth and differentiation of ovarian cells neglected an important aspect of ovarian physiology, namely ovarian cell apoptosis. The article by (Vaskivuo and Tapanainen, 2003) summarizes ‘normal’ death (or apoptosis) of ovarian cells during development and the role of hormonal systems in the regulation of apoptosis signalling pathways important in the regulation of follicle atresia. Finally, Ben-Shlomo, (Ben-Shlomo, 2003) proposed the use of intracellular signalling pathway analyses to elucidate the molecular basis of a pathological condition in the ovary. He discussed the role of genes in the insulin signalling pathway associated with polycystic ovarian syndrome (PCOS). This
13
Symposium - Analysis of ovarian signalling pathways - AJW Hsueh
article emphasizes the importance of the analysis of differential usage and potential abnormality of genes in the insulin signalling pathway in peripheral and ovarian tissues of patients with PCOS. With recent advances in genomics, one can anticipate the identification of ovarian paralogous genes in diverse signalling pathways, together with the high throughput analysis of ovarian gene expression pattern in normal and diseased ovaries. The eventual integration of physiological and pathological data in different ovarian cell types will allow rapid advances in ovarian genomics and the elucidation of molecular defects leading to ovarian diseases such as polycystic ovarian syndrome and premature ovarian failure. These advances could also allow improved treatment of human infertility associated with ovarian dysfunctions.
14
References Ben-Shlomo I, Vitt UA, Hsueh AJW 2002 Perspective: the ovarian kaleidoscope database-II. Functional genomic analysis of an organ-specific database. Endocrinology 143, 2041–2044. Ben-Shlomo I 2003 The polycystic ovary syndrome: What insulin resistance got to do with it? Reproductive BioMedicine Online 6, 36–42 – this issue. LaPolt PS, Leung K, Ishimaru R et al. 2003 Roles of cyclic GMP in modulating ovarian functions. Reproductive BioMedicine Online 6, 15–23 – this issue. Leo CP, Hsu SY, Hsueh AJW 2002 Hormonal genomics. Endocrine Reviews 23, 369–381. Vaskivuo TE, Tapanainen JS 2003 Apoptosis in the human ovary. Reproductive BioMedicine Online 6, 24–35– this issue.