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Rapid Effects of LH on Gene Expression in the Mural Granulosa Cells of Mouse Periovulatory Follicles REPRODUCTIONRESEARCH Rapid effects of LH on gene expression in the mural granulosa cells of mouse periovulatory follicles Martha Z Carletti and Lane K Christenson Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3075 KLSIC, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA Correspondence should be addressed to L K Christenson; Email: [email protected] Abstract LH acts on periovulatory granulosa cells by activating the PKA pathway as well as other cell signaling cascades to increase the transcription of specific genes necessary for ovulation and luteinization. Collectively, these cell signaling responses occur rapidly (within minutes); however, presently no high throughput studies have reported changes before 4 h after the LH surge. To identify early response genes that are likely critical for initiation of ovulation and luteinization, mouse granulosa cells were collected before and 1 h after hCG. Fifty-seven gene transcripts were significantly (P!0.05) upregulated and three downregulated following hCG. Twenty-four of these transcripts were known to be expressed after the LH/hCG surge at later time points, while 36 were unknown to be expressed by periovulatory granulosa cells. Temporal expression of several transcripts, including the transcription factors Nr4a1, Nr4a2, Egr1, Egr2, Btg1, and Btg2, and the epidermal growth factor (EGF)-like ligands Areg and Ereg, were analyzed by quantitative RT-PCR, and their putative roles in granulosa cell function are discussed. Epigen (Epgn), another member of the family of EGF-like ligands was identified for the first time in granulosa cells as rapidly induced by LH/hCG. We demonstrate that Epgn initiates cumulus expansion, similar to the other EGF-receptor ligands Areg and Ereg. These studies illustrate that a number of changes in gene expression occur in vivo in response to LH, and that many of the differentially expressed genes are transcription factors that we would predict in turn modulate granulosa cell gene expression to ultimately impact the processes of ovulation and luteinization. Reproduction (2009) 137 843–855 Introduction surge, the transcriptional changes occurring in granulosa cells in the moments immediately (within 1 h) after the LH activates a number of cellular signaling cascades LH surge are not well defined. within the preovulatory granulosa cell, including the Global gene expression analyses at the later time points canonical PKA pathway (Bachelot & Binart 2005). These after LH have yielded a wealth of information about genes pathways induce changes in gene expression that that were not known to be involved in ovarian function. ultimately cause phenotypic and physiological changes For example, Espey & Richards (2002) have linked the in the cells, culminating in ovulation and luteinization. expression of many genes previously unknown to be These molecular changes include the coordinated regulated by LH in the rat ovary through the use of RT-PCR expression of a number of genes important for, among differential display. They identified the epidermal growth other events, the shift from estrogen synthesis to factor (EGF)-like ligand, epiregulin (Ereg), as being induced progesterone synthesis, the structural remodeling of the by LH, and subsequent studies have demonstrated that follicle, and the maturation of the oocyte. A number of Ereg and several other EGF-like growth factors, amphir- genes known to be critical for ovulation and luteiniza- egulin (Areg), and betacellulin (Btc ) are important for tion have been identified downstream of the LH surge, oocyte maturation and cumulus expansion (Espey & including early growth regulatory factor-1 (Egr1; Espey Richards 2002, Park et al.2004). A sample of 20 genes et al. 2000), CCAAT enhancer binding protein b (Cebpb; differentially regulated at various time points after LH (2, 4, Sirois & Richards 1993), cyclin D2 (Sicinski et al. 1996), 8, 12, and 24 h) in rat whole ovary were reported; however, Star (Clark & Stocco 1995), and progesterone receptor a comprehensive list has not yet been published (Espey & (Park & Mayo 1991). Disruption of these genes in the Richards 2002). In another study, suppression subtractive mouse leads to either failure to ovulate or luteinization hybridization analysis in mice yielded 36 ovary-specific defects (Sterneck et al. 1997, Richards et al. 1998). genes, 22 of which were under hormonal regulation, as However, while most of these critical genes have been indicated by their expression 3, 6, 9, 12, 24, and 48 h after shown to be upregulated between 2 and 6 h after the LH hCG (Hennebold et al. 2000). McRae et al. (2005) used q 2009 Society for Reproduction and Fertility DOI: 10.1530/REP-08-0457 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/26/2021 04:46:48AM via free access 844 M Z Carletti and L K Christenson serial analysis of gene expression in mouse granulosa cells detected at 1 h versus that at 0 h following hCG before and 12 h after hCG treatment, and identified four treatment. Seventy-three genes exhibited a statistical genes not previously known to be expressed in the difference in total RNA levels between 0 and 1 h, with 70 granulosa cells. Finally, microarray analysis performed genes statistically upregulated 1 h after hCG and three before and 6 h after hCG treatment in rat granulosa cells genes statistically downregulated (Fig. 1). However, due identified several more LH-regulated targets, including to redundancy of the oligonucleotide probes on the 430A cutaneous fatty acid-binding protein, a factor important in chip, only 60 independent genes were differentially lipid metabolism (Leo et al.2001). Since the advent of regulated (57 upregulated and three downregulated). global gene expression analysis methods, researchers have Table 1 depicts twenty-four genes that were previously primarily focused on time points 3–12 h after the LH surge known to be expressed in the ovary, and these genes (Richards et al.1998, Espey & Richards 2002, McRae et al. were grouped by their putative ovarian function based on 2005). In the one exception, Kawamura et al.(2005),using the previous publications (Table 1). Table 2 depicts the a very comprehensive array approach, identified brain- remaining 36 gene transcripts that were identified for derived neurotrophic factor as an LH-regulated gene. In the first time within the ovary, and more specifically 2008, the same array data was used again to identify within granulosa cells. In Table 2, genes were grouped fractalkine (Zhao et al.2008); however, with the exception by their molecular function within gene ontology. of these two genes the results of these arrays have yet to be Temporal gene expression profiles were determined released. for a subset of these identified genes using qRT-PCR on Therefore, to date, no comprehensive gene expression samples collected throughout the periovulatory period array analysis of the murine periovulatory granulosa cells 1 1 (0, ⁄4 , ⁄2 , 1, 2, 4, 8, and 12 h post-hCG). The correlation has been published at any time point earlier than 6 h coefficient on the array versus the sixteen genes analyzed after LH. However, northern blot and quantitative by qRT-PCR at 1 h post-hCG was rZ0.6825 (P!0.0001). RT-PCR (qRT-PCR) analyses of differential display studies and individual gene analysis studies have shown that many of the genes identified at later time points were EGF-like ligands are rapidly upregulated after LH/hCG upregulated earlier. For example, the mRNA levels of the The genes encoding the EGF-like ligands, amphiregulin transcription factor Egr1 and the acute early response (Areg), epiregulin (Ereg), and epigen (Epgn) were dramati- gene 5-aminolevulinate synthase increased within 1 h cally upregulated 1 h after hCG. Areg had the highest after hCG treatment (Espey et al. 2000, Park et al. 2003). induction of all genes present on the array with an The rapid expression of Egr1 has been associated with 81.2-fold induction 1 h after hCG, while Ereg was the increased transcription of a number of other genes that modulate the ovulatory and luteinization processes, and its importance in these processes is emphasized in Egr1- null mice that are infertile due to a lack of both ovulation and luteinization (Richards et al. 2002). This suggests that there is an unexplored realm of LH-regulation that occurs in the early minutes to hours after the LH surge and these rapidly (and often transiently) upregulated genes may be playing a necessary, as of yet unidentified, role in ovulation and luteinization. In this report, we utilized microarray gene expression analysis to identify rapidly LH-induced genes in mouse granulosa cells. We anticipate that the genes identified here will be pivotal to understanding the cascades of coordinated gene expression that occur in granulosa cells in response to the LH surge. Results LH/hCG rapidly affects gene expression in granulosa cells Figure 1 Sixty genes were differentially expressed between 0 and 1 h Of the 22 690 genes and ESTs on the Affymetrix post-hCG. Genes present in three out of the four microarrays are categorized with the averaged log intensity for all the steady state microarray chips, 43% were identified as present in at transcripts along the horizontal axis, and the log ratio of signal intensity least three out of the four steady state samples for both 0 for each gene between 0 and 1 h on the vertical axis (NIA Array and 1 h. The induction ratio for each of the 9756 genes Analysis). Upregulated genes are indicated as red spots and down- was determined by calculating the ratio of signal regulated genes as green spots. Reproduction (2009) 137 843–855 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/26/2021 04:46:48AM via free access Rapid effects of LH on granulosa cell gene expression 845 Table 1 Genes previously identified in the ovary and here shown by microarray to be differentially expressed* 1 h after hCG.
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