title: Prox1 regulates the notch1-mediated inhibition of neurogenesis.
abstract: Activation of Notch1 signaling in neural progenitor cells (NPCs) induces self-renewal and inhibits neurogenesis. Upon neuronal differentiation, NPCs overcome this inhibition, express proneural genes to induce Notch ligands, and activate Notch1 in neighboring NPCs. The molecular mechanism that coordinates Notch1 inactivation with initiation of neurogenesis remains elusive. Here, we provide evidence that Prox1, a transcription repressor and downstream target of proneural genes, counteracts Notch1 signaling via direct suppression of Notch1 gene expression. By expression studies in the developing spinal cord of chick and mouse embryo, we showed that Prox1 is limited to neuronal precursors residing between the Notch1+ NPCs and post-mitotic neurons. Physiological levels of Prox1 in this tissue are sufficient to allow binding at Notch1 promoter and they are critical for proper Notch1 transcriptional regulation in vivo. Gain-of-function studies in the chick neural tube and mouse NPCs suggest that Prox1-mediated suppression of Notch1 relieves its inhibition on neurogenesis and allows NPCs to exit the cell cycle and differentiate. Moreover, loss-of-function in the chick neural tube shows that Prox1 is necessary for suppression of Notch1 outside the ventricular zone, inhibition of active Notch signaling, down-regulation of NPC markers, and completion of neuronal differentiation program. Together these data suggest that Prox1 inhibits Notch1 gene expression to control the balance between NPC self-renewal and neuronal differentiation.
authors.affiliation: Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Valeria
authors.initials: V
authors.lastname: Kaltezioti
authors.forename: Georgia
authors.initials: G
authors.lastname: Kouroupi
authors.forename: Maria
authors.initials: M
authors.lastname: Oikonomaki
authors.forename: Evangelia
authors.initials: E
authors.lastname: Mantouvalou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Stergiopoulos
authors.forename: Aristidis
authors.initials: A
authors.lastname: Charonis
authors.forename: Hermann
authors.initials: H
authors.lastname: Rohrer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Matsas
authors.forename: Panagiotis K
authors.initials: PK
authors.lastname: Politis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D054259:Neural Tube / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D055495:Neurogenesis; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein