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Role of Estrogen Receptor Beta in Neural Differentiation of Mouse Embryonic Stem Cells

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Role of Estrogen Receptor Beta in Neural Differentiation of Mouse Embryonic Stem Cells Role of estrogen receptor beta in neural differentiation PNAS PLUS of mouse embryonic stem cells Mukesh K. Varshneya, José Inzunzaa, Diana Lupua,b,c, Vaidheeswaran Ganapathya,b, Per Antonsona, Joëlle Rüeggb,d, Ivan Nalvartea,1,2, and Jan-Åke Gustafssona,e,1,2 aDepartment of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden; bSwetox, Unit of Toxicology Sciences, Karolinska Institutet, 151 36 Södertälje, Sweden; cDepartment of Toxicology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; dCenter for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 171 64 Solna, Sweden; and eCenter for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204 Contributed by Jan-Åke Gustafsson, October 25, 2017 (sent for review August 10, 2017; reviewed by Luis M. Garcia-Segura and Stephen Safe) The ability to propagate mature cells and tissue from pluripotent in layers II–IV of the somatosensory cortex, which persists in aged stem cells offers enormous promise for treating many diseases, mice (13, 14). However, adult mice lacking ERβ display increased including neurodegenerative diseases. Before such cells can be vulnerability to neurodegeneration (15, 16), increased anxiety-like used successfully in neurodegenerative diseases without causing behavior (17, 18), perturbed serotonin levels in several brain re- unwanted cell growth and migration, genes regulating growth gions, and lower dopamine levels in the caudate putamen (17), an and migration of neural stem cells need to be well characterized. area of the midbrain implicated in Parkinson’sdisease,aswellas Estrogen receptor beta (ERβ) is essential for migration of neurons behavioral deficits related to impaired spatial learning (18, 19). and glial cells in the developing mouse brain. To examine whether These changes are not observed in ERα-KO mice (which instead ERβ influences differentiation of mouse embryonic stem cells show abnormal behavior linked to reproduction), indicating that (mESC) into neural lineages, we compared control and ERβ knock- ERβ serves as the main ER isoform in regulating neuronal devel- out (BERKO) mESCs at defined stages of neural development and opment associated with affective behaviors and cognition. Investi- examined the effects of an ERβ-selective ligand (LY3201) with a gations in mice and rats also indicate that both ERα and ERβ are combination of global and targeted gene-expression profiling and specifically expressed not only in neurons but also in glial cells in the expression of key pluripotency markers. We found that ERβ different brain areas during development (20). ERβ is expressed was induced in embryoid bodies (EBs) and neural precursor cells before the onset of E2 synthesis in the embryonic mouse brain (9) MEDICAL SCIENCES (NPCs) during development. Proliferation was higher in BERKO and may affect the cortical layering even though E2 is not present. NPCs and was inhibited by LY3201. Neurogenesis was reduced in Also, estradiol-independent activation of ERβ is evidenced by the BERKO ES cells, and oligodendrogliogenesis was enhanced. BERKO fact that aromatase-knockout mice (Ar-KO), which are incapable of EBs expressed higher levels of key ectodermal and neural progen- synthesizing E2, do not show any major aberrations in brain struc- itor markers and lower levels of markers for mesoderm and endo- ture (21). Although it is expressed early in embryonal brain devel- β derm lineages. ER -regulated factors are involved in cell adhesion, opment, a detailed molecular study of the functions of ERβ during axon guidance, and signaling of Notch and GABA receptor path- neural development remains to be performed. ways, as well as factors important for the differentiation of neuro- In the present study, we used mouse ES cells (mESCs) from WT nal precursors into dopaminergic neurons (Engrailed 1) and for the β β β and ER -KO (BERKO) mice to delineate the role of ER in oligodendrocyte fate acquisition (Olig2). Our data suggest that ER neural differentiation. We used highly controlled culture conditions is an important component for differentiation into midbrain neu- rons as well as for preventing precocious oligodendrogliogenesis. Significance stem cell | estrogen receptor beta | dopamine | oligodendrocyte | midbrain Controlling the proliferation and proper fate acquisition of plu- ripotent stem cells is a major challenge in regenerative therapies ifferentiation of neural precursor cells (NPCs) into specific today. Our study reveals that the estrogen receptor beta (ERβ)is neurons and glial cells is the basis for cell-replacement therapy D an important factor in maintaining the neuroepithelial and in neurological disorders such as Parkinson’s disease (1–3). Al- midbrain stem cell pools by repressing proliferation and early though successful transplantation of NPCs in animal models of ’ – nonneuronal fate acquisition. We report on the factors that Parkinson s disease has been done (1 3), their clinical use is still underlie these effects of ERβ. Further, we report that ERβ facil- limited due to challenges such as stem cell tumorigenesis. There- itates midbrain dopaminergic fate and function. The data pre- fore, more studies are necessary to understand NPC differentiation, sented in this study suggest that ERβ is a factor to be considered proliferation, and maintenance. One factor that may play an im- in designing regenerative therapies for example neurodegen- portant role here is the ovarian steroid hormone 17β-estradiol erative diseases such as Parkinson’s disease. (estrogen, E2), which has shown beneficial effects in ameliorating neurodegeneration in animal models (4, 5) and is involved in the Author contributions: I.N. conceived the study; J.I., I.N., and J.-Å.G. designed research; survival of midbrain dopaminergic neurons and neurotransmitter M.K.V., D.L., V.G., P.A., and I.N. performed research; J.I., J.R., I.N., and J.-Å.G. contributed new reagents/analytic tools; M.K.V., J.I., D.L., J.R., and I.N. analyzed data; and M.K.V., J.R., synthesis and catabolism (6). I.N., and J.-Å.G. wrote the paper. Estrogenic actions are mediated mainly through two distinct Reviewers: L.M.G.-S., Instituto Cajal; and S.S., Texas A&M University. estrogen receptor (ER) subtypes: ERα and ERβ. Both ERs are The authors declare no conflict of interest. expressed in the CNS. ERα is the predominant ER in the hypo- Published under the PNAS license. thalamus, arcuate nucleus, and preoptic area, controlling re- β Data deposition: The microarray data are accessible through Gene Expression Omnibus production (7), while ER influences nonreproductive processes (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE103312). in the brain. It is the main ER expressed in the cerebral cortex, 1 – I.N. and J.-Å.G. contributed equally to this work. hippocampus, and the dorsal raphe (8 10), where it modulates 2 β To whom correspondence may be addressed. Email: [email protected] or jgustafs@ tryptophan hydroxylase (Tph2) levels (11, 12). ER knockout in central.uh.edu. mice affects cortical layering and migration of newly formed This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. neurons at later stages of corticogenesis, resulting in hypocellularity 1073/pnas.1714094114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1714094114 PNAS Early Edition | 1of10 Downloaded by guest on September 23, 2021 to differentiate mESCs toward defined stages of midbrain neu- differentiation day 10 (Fig. 1). Both WT and BERKO NPCs ac- rogenesis, allowing systematic investigation of the effect of loss of quired typical neural tube rosette-like morphology and expressed ERβ during this process via global and targeted gene-expression the NSC markers Nestin and Sox2 (SI Appendix,Fig.S5A). At this profiling. We report that ERβ is necessary for maintaining neural stage very few cells were positive for Tubb3, a marker for differ- stem cell (NSC) proliferation and self-renewal, likely through entiated neurons (SI Appendix,Fig.S5B), confirming that both Notch–Hes signaling, as well as for decisions of dopaminergic– WT and BERKO NPCs constituted a population dominated serotonergic neuron specification and function. In addition, the by NSCs. loss of ERβ resulted in the enhanced expression of genes involved We found that proliferation was higher in BERKO NPCs than in precocious oligodendrogliogenesis. in WT cells (Fig. 2A), with no measurable differences in apo- ptosis between the genotypes (Fig. 2B). The ERβ-selective ago- Results nist LY3201 (optimal dose set to 0.5 nM) (SI Appendix, Fig. S5C) Pluripotency Characterization of BERKO mESCs and Embryoid Bodies. (22) lowered WT NPC proliferation by ∼50% but had no effect Female mESCs from WT and BERKO mice were genotyped to on BERKO cells (Fig. 2A). The increased BERKO NPC pro- confirm ERβ knockout (SI Appendix, Fig. S1 A, D, and E) and liferation was accompanied by decreased expression of the were adapted to feeder-free culture conditions in a chemically cyclin-dependent kinase (CDK) inhibitors and cell-cycle regula- defined two-inhibitor medium (2i: MEK and GSK3β inhibitors) tors p27kip1 and p21cip1 in BERKO NPCs, which promote G1–S in the presence of leukemia inhibitory factor (LIF). The mESCs phase transitions (Fig. 2C). LY3201 treatment had no effects on were then differentiated (Materials and Methods and Fig. 1) to the expression of these regulators in both genotypes, suggesting four defined stages along the midbrain neuronal lineage com- that ERβ functions independently of ligand activation or that the mitment: embryoid body (EB), NPC/NSC, midbrain precursor cells synthesize endogenous estradiol. However, the expression cell (mDPC), and midbrain neuron (MN) (Fig. 1). The absence of aromatase (Cyp19a1) in EBs and NPCs was very low, at the of ERβ in BERKO cultures was confirmed by immunocyto- limit of detection (SI Appendix, Fig. S5D and Dataset S2), which chemistry (SI Appendix, Fig. S1B), qPCR (SI Appendix, Fig. suggests that ERβ may work predominantly independently of S1C), and Western blotting (SI Appendix, Fig. S1F). ERβ was not ligand activation during early neural differentiation.
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