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The Progestin Receptor Interactome in the Female Mouse Hypothalamus: Interactions with Synaptic Proteins Are Isoform Specific and Ligand Dependent

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The Progestin Receptor Interactome in the Female Mouse Hypothalamus: Interactions with Synaptic Proteins Are Isoform Specific and Ligand Dependent New Research Integrative Systems The Progestin Receptor Interactome in the Female Mouse Hypothalamus: Interactions with Synaptic Proteins Are Isoform Specific and Ligand Dependent Kalpana D. Acharya,1 Sabin A. Nettles,1 Katherine J. Sellers,2 Dana D. Im,1 Moriah Harling,1 Cassandra Pattanayak,3 Didem Vardar-Ulu,4 Cheryl F. Lichti,5 Shixia Huang,6 Dean P. Edwards,6 Deepak P. Srivastava,2 Larry Denner,7 and Marc J. Tetel1 DOI:http://dx.doi.org/10.1523/ENEURO.0272-17.2017 1Neuroscience Program, Wellesley College, Wellesley, MA 02481, USA, 2Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neurosciences Institute, Institute of Psychiatry, Psychology and Neuroscience, and MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK, 3Quantitative Analysis Institute, Departments of Mathematics and Quantitative Reasoning, Wellesley College, Wellesley, MA 02481, USA, 4Chemistry Department, Boston University, Boston, MA 02215, USA, 5Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, 6Department of Molecular and Cellular Biology, Department of Pathology and Immunology, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA, and 7Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA Abstract Progestins bind to the progestin receptor (PR) isoforms, PR-A and PR-B, in brain to influence development, female reproduction, anxiety, and stress. Hormone-activated PRs associate with multiple proteins to form functional complexes. In the present study, proteins from female mouse hypothalamus that associate with PR were isolated using affinity pull-down assays with glutathione S-transferase–tagged mouse PR-A and PR-B. Using complementary proteomics approaches, reverse phase protein array (RPPA) and mass spectrometry, we identified hypothalamic proteins that interact with PR in a ligand-dependent and isoform-specific manner and were confirmed by Western blot. Synaptic proteins, including synapsin-I and synapsin-II, interacted with agonist- bound PR isoforms, suggesting that both isoforms function in synaptic plasticity. In further support, synaptogyrin- III and synapsin-III associated with PR-A and PR-B, respectively. PR also interacted with kinases, including c-Src, mTOR, and MAPK1, confirming phosphorylation as an integral process in rapid effects of PR in the brain. Consistent with a role in transcriptional regulation, PR associated with transcription factors and coactivators in a ligand-specific and isoform-dependent manner. Interestingly, both PR isoforms associated with a key regulator of energy homeostasis, FoxO1, suggesting a novel role for PR in energy metabolism. Because many identified Significance Statement Progesterone binds to the progestin receptor (PR) isoforms, PR-A and PR-B, in the brain to profoundly influence female reproduction, brain development, neuroprotection, and stress. We combined mass spectrometry and reverse phase protein arrays to identify mouse hypothalamic proteins that function in synaptic plasticity, transcription, translation, and energy metabolism and interacted with PR in a ligand- dependent and isoform-specific manner. In addition, progesterone increased synaptic density in primary cortical neurons, suggesting a function for progesterone in synapse formation in cortical neurons. Taken together, these findings provide evidence for novel functions of PR in synaptic modulation and energy homeostasis to affect health and disease. September/October 2017, 4(5) e0272-17.2017 1–19 New Research 2 of 19 proteins in this PR interactome are synaptic proteins, we tested the hypothesis that progestins function in synaptic plasticity. Indeed, progesterone enhanced synaptic density, by increasing synapsin-I–positive synapses, in rat primary cortical neuronal cultures. This novel combination of RPPA and mass spectrometry allowed identification of PR action in synaptic remodeling and energy homeostasis and reveals unique roles for progestins in brain function and disease. Key words: Cortex; estrogen; progesterone; proteomics; synapse; synapsin Introduction though PR-A in the mouse hypothalamus is the primary Progestins, a class of steroid hormones, act in the brain mediator of female sexual behavior, both isoforms are to profoundly influence development (Beyer et al., 2002; required for the full behavioral response (Mani et al., Wagner, 2006); neuroprotection (Stein and Hoffman, 2003; 2006). In support, PR-A and PR-B are differentially Singh, 2006; Irwin et al., 2008; Su et al., 2012); reproductive expressed in the female mouse hypothalamus (Acharya behavior (Sinchak and Micevych, 2001; Blaustein, 2008); et al., 2015). learning, memory, and cognition (Hull et al., 1980; Sand- PR associate with multiple proteins, including nuclear strom and Williams, 2001; Wagner, 2006); and anxiety and receptor coactivators, which stabilize the receptor com- stress (Mora et al., 1996; Blaustein and Ismail, 2013; Keyes plex and enhance transcription (Hill et al., 2012; Goswami et al., 2013; Uphouse et al., 2013). In addition, progestins et al., 2014; Simons et al., 2014). In the female mouse have been implicated in a variety of human diseases, includ- hypothalamus, the PR isoforms are differentially ex- ing neurodegeneration and breast cancer (Richer et al., pressed with steroid receptor coactivator-1 (SRC-1, also 2002; Brinton et al., 2008; Obr and Edwards, 2012; Diep named NCOA1) and SRC-2 (NCOA2; Acharya et al., et al., 2015). 2015). In addition, SRC-1 and SRC-2 from hypothalamus Progestins elicit many of their effects by binding to associate with the PR isoforms in a ligand-dependent and progestin receptors (PR), which exist as two isoforms in isoform-specific manner (Molenda-Figueira et al., 2008; mammals, an N-terminally truncated PR-A and a full- Yore et al., 2010) and modulate hormone-dependent gene length PR-B (Tetel and Lange, 2009). Both isoforms share expression and female sexual behavior (Apostolakis et al., a C-terminal ligand binding domain, a DNA binding do- 2002; Molenda et al., 2002; Molenda-Figueira et al., 2006). main, and two transactivation domains (Horwitz et al., Taken together, these studies indicate that nuclear recep- 1990; Kastner et al., 1990). Interestingly, a third transac- tor coactivators are important in PR function in the brain. tivation domain exclusive to PR-B, and a PR-A specific PR act through both classic and nonclassic pathways in inhibitory region, have been identified, allowing differ- the brain and other progestin-responsive tissues. For ex- ential functions by the isoforms (Hovland et al., 1998). ample, in the hypothalamus, PR activation induces lordo- Isoform-specific transcriptional activation by PR has sis in female rodents through transcriptional regulation been observed in vitro and in vivo (Sartorius et al., 1994; (Leonhardt et al., 2003; Molenda-Figueira et al., 2006)as Giangrande et al., 1997; Conneely et al., 2000; Cheng well as nonclassic kinase activation (González-Flores et al., 2001; Richer et al., 2002; Mulac-Jericevic et al., et al., 2004; Mani et al., 2006). PRs are present in syn- 2003). Isoform-specific knockout mice reveal that al- apses (Waters et al., 2008; Mitterling et al., 2010) and rapidly alter dendritic spine densities in rat hippocampus (Woolley and McEwen, 1993; McEwen and Woolley, Received August 2, 2017; accepted September 1, 2017; First published 1994), cortical neurons (Chen et al., 2009; Sanchez et al., September 11, 2017. 2013), and hypothalamus (Griffin et al., 2010). Authors report no conflict of interest. Author contributions: K.D.A., D.V.-U., D.P.S., L.D., and M.J.T. designed Although we are gaining a better understanding of dis- research; K.D.A., S.A.N., K.J.S., D.D.I., C.F.L., S.H., D.P.E., D.P.S., L.D., and tinct functions of the PR isoforms in brain, little is known M.J.T. performed research; K.D.A., S.A.N., K.J.S., M.H., C.P., C.F.L., S.H., about the mechanisms involved. Therefore, to investigate D.P.E., D.P.S., L.D., and M.J.T. analyzed data; and K.D.A., D.P.E., D.P.S., L.D., the factors that could contribute to the differential function and M.J.T. wrote the paper. of the PR isoforms in brain, we have combined mass This work was funded by NIH R01 DK61935 (MJT), MRC MR/L021064/1 (DPS), Cancer Prevention & Research Institute of Texas (CPRIT) Core Facility spectrometry (MS) and reverse phase protein array Support Award (RP170005), and NCI Cancer Center Support Grant to (RPPA) in a functional proteomic analysis to identify pro- Antibody-based Proteomics Core/Shared Resource (P30CA125123; DPE and teins from adult female mouse hypothalamus that interact SH). with mouse PR-A and PR-B. In addition, given the iden- Acknowledgments: We thank Fuli Jia, Kimberley Holloway, and Davis So of the Antibody-based Proteomics Core/Shared Resource at Baylor College of tification of many synaptic proteins that interact with PR in Medicine for their excellent technical assistance with RPPA assays and Dr. the present study, we tested the hypothesis that proges- William Russell of the Proteomics Core of the University of Texas Medical tins influence synaptic plasticity by increasing synapse Branch for helpful discussions. formation in cortical neurons. Correspondence should be addressed to Kalpana D. Acharya, Neuroscience Program, Wellesley College, 106 Central St, Wellesley, MA 02481. E-mail: [email protected]. Materials and Methods DOI:http://dx.doi.org/10.1523/ENEURO.0272-17.2017 Copyright © 2017 Acharya et al.
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