title: Habenular Neurogenesis in Zebrafish Is Regulated by a Hedgehog, Pax6 Proneural Gene Cascade.
abstract: The habenulae are highly conserved nuclei in the dorsal diencephalon that connect the forebrain to the midbrain and hindbrain. These nuclei have been implicated in a broad variety of behaviours in humans, primates, rodents and zebrafish. Despite this, the molecular mechanisms that control the genesis and differentiation of neural progenitors in the habenulae remain relatively unknown. We have previously shown that, in zebrafish, the timing of habenular neurogenesis is left-right asymmetric and that in the absence of Nodal signalling this asymmetry is lost. Here, we show that habenular neurogenesis requires the homeobox transcription factor Pax6a and the redundant action of two proneural bHLH factors, Neurog1 and Neurod4. We present evidence that Hedgehog signalling is required for the expression of pax6a, which is in turn necessary for the expression of neurog1 and neurod4. Finally, we demonstrate by pharmacological inhibition that Hedgehog signalling is required continuously during habenular neurogenesis and by cell transplantation experiments that pathway activation is required cell autonomously. Our data sheds light on the mechanism underlying habenular development that may provide insights into how Nodal signalling imposes asymmetry on the timing of habenular neurogenesis.
authors.affiliation: Université de Toulouse III, UPS, Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), 118 route de Narbonne, F-31062 Toulouse, France.|CNRS, CBD UMR 5547, F-31062 Toulouse, France.|Stanford University, School of Medicine, 269-279 Campus Drive, Stanford, CA 94305, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Halluin
authors.affiliation: Université de Toulouse III, UPS, Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), 118 route de Narbonne, F-31062 Toulouse, France.|CNRS, CBD UMR 5547, F-31062 Toulouse, France.|Stanford University, School of Medicine, 269-279 Campus Drive, Stanford, CA 94305, United States of America.
authors.forename: Romain
authors.initials: R
authors.lastname: Madelaine
authors.affiliation: Unit of Molecular Biology and Genetic Engineering, University of Liège, GIGA-R, B34, Avenue de l'Hôpital 1, B-4000 Liège, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Naye
authors.affiliation: Unit of Molecular Biology and Genetic Engineering, University of Liège, GIGA-R, B34, Avenue de l'Hôpital 1, B-4000 Liège, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Peers
authors.affiliation: Université de Toulouse III, UPS, Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), 118 route de Narbonne, F-31062 Toulouse, France.|CNRS, CBD UMR 5547, F-31062 Toulouse, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Roussigné
authors.affiliation: Université de Toulouse III, UPS, Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), 118 route de Narbonne, F-31062 Toulouse, France.|CNRS, CBD UMR 5547, F-31062 Toulouse, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Blader
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D019521:Body Patterning; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D019262:Habenula / Q000196:embryology*; D053823:Hedgehog Proteins / Q000502:physiology*; D006579:Heterozygote; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D000071841:PAX6 Transcription Factor / Q000502:physiology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D014157:Transcription Factors; D029961:Zebrafish Proteins; C476737:neurod4 protein, zebrafish; C486337:neurog1 protein, zebrafish