title: Pbx1 is required for adult subventricular zone neurogenesis.
abstract: TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron-specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2.
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany.
authors.forename: Britta Moyo
authors.initials: BM
authors.lastname: Grebbin
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Hau
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Groß
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Anders-Maurer
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Schramm
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Koss
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wille
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA Program in Craniofacial Biology, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, Departments of Orofacial Sciences and Anatomy, University of California, San Francisco, 513 Parnassus Avenue, HSW 710, San Francisco, CA 94143, USA.
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.affiliation: Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany dorothea.schulte@kgu.de.
authors.forename: Dorothea
authors.identifier: 0000-0002-7243-6319
authors.initials: D
authors.lastname: Schulte
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004742:Enhancer Elements, Genetic / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D020547:Lateral Ventricles / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C481797:Pbx1 protein, mouse; C490382:Pbx2 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C090466:proto-oncogene protein Pbx3; D014446:Tyrosine 3-Monooxygenase
keywords: Adult neurogenesis; Cell fate specification; Doublecortin; Pioneer factor; Subventricular zone; TALE-homeodomain protein