title: The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells.
abstract: Successful haematopoiesis requires long-term retention of haematopoietic stem cells (HSCs) in a quiescent state. The transcriptional regulation of stem cell quiescence, especially by factors with specific functions in HSCs, is only beginning to be understood. Here, we demonstrate that Nurr1, a nuclear receptor transcription factor, has such a regulatory role. Overexpression of Nurr1 drives early haematopoietic progenitors into quiescence. When stem cells overexpressing Nurr1 are transplanted into lethally irradiated mice, they localize to the bone marrow, but do not contribute to regeneration of the blood system. Furthermore, the loss of only one allele of Nurr1 is sufficient to induce HSCs to enter the cell cycle and proliferate. Molecular analysis revealed an association between Nurr1 overexpression and upregulation of the cell-cycle inhibitor p18 (also known as INK4C), suggesting a mechanism by which Nurr1 could regulate HSC quiescence. Our findings provide critical insight into the transcriptional control mechanisms that determine whether HSCs remain dormant or enter the cell cycle and begin to proliferate.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Sirin
authors.forename: Georgi L
authors.initials: GL
authors.lastname: Lukov
authors.forename: Rui
authors.initials: R
authors.lastname: Mao
authors.forename: Orla M
authors.initials: OM
authors.lastname: Conneely
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
mesh_terms: D000818:Animals; D001853:Bone Marrow; D002453:Cell Cycle; D049109:Cell Proliferation; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2