title: The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes.
abstract: Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator Id3 decreased the number of astrocytes generated from SVZ-derived adult NSPCs in the cortical lesion area after traumatic brain injury. Cortical brain injury resulted in rapid BMP-2 and Id3 up-regulation in the SVZ stem cell niche. Id3(-/-) adult NSPCs failed to differentiate into BMP-2-induced astrocytes, while NSPCs deficient for the Id3-controlled transcription factor E47 readily differentiated into astrocytes in the absence of BMP-2. Mechanistically, E47 repressed the expression of several astrocyte-specific genes in adult NSPCs. These results identify Id3 as the BMP-2-induced transcriptional regulator, promoting adult NSPC differentiation into astrocytes upon CNS injury and reveal a molecular link between environmental changes and NSPC differentiation in the CNS after injury.
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bohrer
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pfurr
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Könül
authors.initials: K
authors.lastname: Mammadzada
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schildge
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Leandra
authors.initials: L
authors.lastname: Plappert
authors.affiliation: Faculty of Biology, University of Freiburg, Freiburg, Germany Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Hils
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Pous
authors.affiliation: Faculty of Biology, University of Freiburg, Freiburg, Germany Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Rauch
authors.affiliation: Department of Dermatology, Medical Center, Freiburg Institute for Advanced Studies (FRIAS), ZBSA Center for Biological Systems Analysis, BIOSS Center for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Verónica I
authors.initials: VI
authors.lastname: Dumit
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Department of Dermatology, Medical Center, Freiburg Institute for Advanced Studies (FRIAS), ZBSA Center for Biological Systems Analysis, BIOSS Center for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kirsch
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schachtrup
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany christian.schachtrup@anat.uni-freiburg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Schachtrup
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis / Q000235:genetics; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D051796:Inhibitor of Differentiation Proteins; D058127:Transcription Factor 3; C067679:Idb3 protein, mouse
keywords: astrocyte‐specific genes; basic helix–loop–helix transcription factor; bone morphogenetic protein; traumatic brain injury; vascular damage