PMID- 30214018 OWN - NLM STAT- MEDLINE DCOM- 20191031 LR - 20201209 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 Sep 13 TI - Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions. PG - 13790 LID - 10.1038/s41598-018-31696-9 [doi] LID - 13790 AB - Groucho related gene 5 (GRG5) is a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. Here, we describe a previously unknown role of GRG5 in early developmental stages by analyzing its function in stem cell fate decisions. By both loss and gain of function approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem Cell (ESC) pluripotent state whereas its overexpression leads to enhanced self-renewal and acquisition of cancer cell-like properties. The malignant characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its pro-oncogenic potential. Furthermore, transcriptomic analysis and cell differentiation approaches underline GRG5 as a multifaceted signaling regulator that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5 promotes neuroectodermal specification via Wnt and BMP signaling suppression. Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor and a neural fate specifier. FAU - Chanoumidou, Konstantina AU - Chanoumidou K AD - Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100, Alexandroupoli, Greece. AD - Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas (FORTH), 70013, Heraklion, Crete, Greece. AD - Lund Stem Cell Center, University Hospital, SE-221 84, Lund, Sweden. FAU - Hadjimichael, Christiana AU - Hadjimichael C AD - Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas (FORTH), 70013, Heraklion, Crete, Greece. FAU - Athanasouli, Paraskevi AU - Athanasouli P AD - Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas (FORTH), 70013, Heraklion, Crete, Greece. AD - Department of Biology, University of Crete, 71409, Heraklion, Crete, Greece. FAU - Ahlenius, Henrik AU - Ahlenius H AUID- ORCID: 0000-0001-8958-6148 AD - Lund Stem Cell Center, University Hospital, SE-221 84, Lund, Sweden. FAU - Klonizakis, Antonis AU - Klonizakis A AD - Department of Biology, University of Crete, 71409, Heraklion, Crete, Greece. FAU - Nikolaou, Christoforos AU - Nikolaou C AD - Department of Biology, University of Crete, 71409, Heraklion, Crete, Greece. FAU - Drakos, Elias AU - Drakos E AD - School of Medicine, University of Crete, 71003, Heraklion, Crete, Greece. FAU - Kostouros, Antonis AU - Kostouros A AD - School of Medicine, University of Crete, 71003, Heraklion, Crete, Greece. FAU - Stratidaki, Irene AU - Stratidaki I AD - Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas (FORTH), 70013, Heraklion, Crete, Greece. FAU - Grigoriou, Maria AU - Grigoriou M AD - Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100, Alexandroupoli, Greece. FAU - Kretsovali, Androniki AU - Kretsovali A AUID- ORCID: 0000-0003-2949-1619 AD - Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas (FORTH), 70013, Heraklion, Crete, Greece. kretsova@imbb.forth.gr. LA - eng GR - 11SYN_10_668/General Secretariat for Research and Technology (GSRT)/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180913 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Co-Repressor Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (Tle5 protein, mouse) RN - 0 (Transcription Factors) SB - IM MH - Animals MH - Cell Differentiation/physiology MH - Cell Proliferation/genetics MH - Cell Transformation, Neoplastic/genetics/*pathology MH - Cells, Cultured MH - Co-Repressor Proteins MH - Embryonic Stem Cells/*cytology MH - Gene Expression Profiling MH - Gene Expression Regulation, Developmental/genetics MH - Mice MH - Neural Plate/*embryology MH - Neural Stem Cells/*cytology MH - Pluripotent Stem Cells/*cytology MH - RNA Interference MH - RNA, Small Interfering/genetics MH - Transcription Factors/genetics/*metabolism MH - Wnt Signaling Pathway PMC - PMC6137157 COIS- The authors declare no competing interests. EDAT- 2018/09/15 06:00 MHDA- 2019/11/02 06:00 PMCR- 2018/09/13 CRDT- 2018/09/15 06:00 PHST- 2017/11/30 00:00 [received] PHST- 2018/08/20 00:00 [accepted] PHST- 2018/09/15 06:00 [entrez] PHST- 2018/09/15 06:00 [pubmed] PHST- 2019/11/02 06:00 [medline] PHST- 2018/09/13 00:00 [pmc-release] AID - 10.1038/s41598-018-31696-9 [pii] AID - 31696 [pii] AID - 10.1038/s41598-018-31696-9 [doi] PST - epublish SO - Sci Rep. 2018 Sep 13;8(1):13790. doi: 10.1038/s41598-018-31696-9.