title: Prox1 regulates Olig2 expression to modulate binary fate decisions in spinal cord neurons.
abstract: Specification of spinal cord neurons depends on gene regulation networks that impose distinct fates in neural progenitor cells (NPCs). Olig2 is a key transcription factor in these networks by inducing motor neuron (MN) specification and inhibiting interneuron identity. Despite the critical role of Olig2 in nervous system development and cancer progression, the upstream molecular mechanisms that control Olig2 gene transcription are not well understood. Here we demonstrate that Prox1, a transcription repressor and downstream target of proneural genes, suppresses Olig2 expression and therefore controls ventral spinal cord patterning. In particular, Prox1 is strongly expressed in V2 interneuron progenitors and largely excluded from Olig2+ MN progenitors (pMN). Gain- and loss-of-function studies in mouse NPCs and chick neural tube show that Prox1 is sufficient and necessary for the suppression of Olig2 expression and proper control of MN versus V2 interneuron identity. Mechanistically, Prox1 interacts with the regulatory elements of Olig2 gene locus in vivo and it is critical for proper Olig2 transcription regulation. Specifically, chromatin immunoprecipitation analysis in the mouse neural tube showed that endogenous Prox1 directly binds to the proximal promoter of the Olig2 gene locus, as well as to the K23 enhancer, which drives Olig2 expression in the pMN domain. Moreover, plasmid-based transcriptional assays in mouse NPCs suggest that Prox1 suppresses the activity of Olig2 gene promoter and K23 enhancer. These observations indicate that Prox1 controls binary fate decisions between MNs and V2 interneurons in NPCs via direct repression of Olig2 gene regulatory elements.
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 115 27, Athens, Greece and.
authors.forename: Valeria
authors.initials: V
authors.lastname: Kaltezioti
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 115 27, Athens, Greece and.
authors.forename: Daphne
authors.initials: D
authors.lastname: Antoniou
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 115 27, Athens, Greece and.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Stergiopoulos
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 115 27, Athens, Greece and.
authors.forename: Ismini
authors.initials: I
authors.lastname: Rozani
authors.affiliation: Research Group Developmental Neurobiology, Max-Planck-Institute for Brain Research, Frankfurt/Main, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Rohrer
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 115 27, Athens, Greece and ppolitis@bioacademy.gr.
authors.forename: Panagiotis K
authors.initials: PK
authors.lastname: Politis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D002642:Chick Embryo; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D007395:Interneurons / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D058953:Neural Stem Cells / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D000076104:Oligodendrocyte Transcription Factor 2; D013116:Spinal Cord / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C512773:Olig2 protein, mouse
keywords: Olig2; V2 interneurons; motor neurons; neural progenitor cells; transcriptional control