title: Sox2 acts in a dose-dependent fashion to regulate proliferation of cortical progenitors.
abstract: Organ formation and maintenance depends on slowly self-renewing stem cells that supply an intermediate population of rapidly dividing progenitors, but how this proliferative hierarchy is regulated is unknown. By performing genome-wide single-cell and functional analyses in the cortex, we demonstrate that reduced Sox2 expression is a key regulatory signature of the transition between stem cells and rapidly dividing progenitors. In stem cells, Sox2 is expressed at high levels, which enables its repression of proproliferative genes, of which Cyclin D1 is the most potent target. Sox2 confers this function through binding to low-affinity motifs, which facilitate the recruitment of Gro/Tle corepressors in synergy with Tcf/Lef proteins. Upon differentiation, proneural factors reduce Sox2 expression, which derepresses Cyclin D1 and promotes proliferation. Our results show how concentration-dependent Sox2 occupancy of DNA motifs of varying affinities translates into recruitment of repressive complexes, which regulate the proliferative dynamics of neural stem and progenitor cells.
authors.affiliation: Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, von Eulers väg 5, 171 77 Stockholm, Sweden.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hagey
authors.affiliation: Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, von Eulers väg 5, 171 77 Stockholm, Sweden. Electronic address: jonas.muhr@licr.ki.se.
authors.forename: Jonas
authors.initials: J
authors.lastname: Muhr
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology*; D019938:Cyclin D1 / Q000378:metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055748:SOXB1 Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: C530105:Ccnd1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D019938:Cyclin D1