title: Tcf7l2 is required for left-right asymmetric differentiation of habenular neurons.
abstract: BACKGROUND
  Although left-right asymmetries are common features of nervous systems, their developmental bases are largely unknown. In the zebrafish epithalamus, dorsal habenular neurons adopt medial (dHbm) and lateral (dHbl) subnuclear character at very different frequencies on the left and right sides. The left-sided parapineal promotes the elaboration of dHbl character in the left habenula, albeit by an unknown mechanism. Likewise, the genetic pathways acting within habenular neurons to control their asymmetric differentiated character are unknown.
  
  
  RESULTS
  In a forward genetic screen for mutations that result in loss of habenular asymmetry, we identified two mutant alleles of tcf7l2, a gene that encodes a transcriptional regulator of Wnt signaling. In tcf7l2 mutants, most neurons on both sides differentiate with dHbl identity. Consequently, the habenulae develop symmetrically, with both sides adopting a pronounced leftward character. Tcf7l2 acts cell automously in nascent equipotential neurons, and on the right side, it promotes dHbm and suppresses dHbl differentiation. On the left, the parapineal prevents this Tcf7l2-dependent process, thereby promoting dHbl differentiation.
  
  
  CONCLUSIONS
  Tcf7l2 is essential for lateralized fate selection by habenular neurons that can differentiate along two alternative pathways, thereby leading to major neural circuit asymmetries.
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hüsken
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Stickney
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Gestri
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Isaac H
authors.initials: IH
authors.lastname: Bianco
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Faro
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Young
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK; Centre de Biologie du Développement (CDB), UPS, Université de Toulouse, 118 Route de Narbonne, 31062, France; CNRS, CDB UMR 5547, 31062 Toulouse, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Roussigne
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hawkins
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Beretta
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: Irena
authors.initials: I
authors.lastname: Brinkmann
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: Alessio
authors.initials: A
authors.lastname: Paolini
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
authors.forename: Raquel
authors.initials: R
authors.lastname: Jacinto
authors.affiliation: Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Shahad
authors.initials: S
authors.lastname: Albadri
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK; Neuroelectronics Research Flanders, 3001 Leuven, Belgium.
authors.forename: Elena
authors.initials: E
authors.lastname: Dreosti
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Matina
authors.initials: M
authors.lastname: Tsalavouta
authors.affiliation: Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Quenten
authors.initials: Q
authors.lastname: Schwarz
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Florencia
authors.initials: F
authors.lastname: Cavodeassi
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Anukampa K
authors.initials: AK
authors.lastname: Barth
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wen
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Centre de Biologie du Développement (CDB), UPS, Université de Toulouse, 118 Route de Narbonne, 31062, France; CNRS, CDB UMR 5547, 31062 Toulouse, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Blader
authors.affiliation: Neuroelectronics Research Flanders, 3001 Leuven, Belgium; Vlaams Instituut voor Biotechnologie, 3001 Leuven, Belgium; KU Leuven, 3001 Leuven, Belgium.
authors.forename: Emre
authors.initials: E
authors.lastname: Yaksi
authors.affiliation: Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Poggi
authors.affiliation: Department of Molecular Evolution and Genomics, Centre for Organismal Studies (COS), Heidelberg University, Im Neuenheimer Feld 329, 69120 Heidelberg, Germany.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Zigman
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, 621 Charles E. Young Drive, Los Angeles, CA 90095, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: s.wilson@ucl.ac.uk.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wilson
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany. Electronic address: matthias.carl@medma.uni-heidelberg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Carl
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000502:physiology; D005786:Gene Expression Regulation; D019262:Habenula / Q000166:cytology / Q000196:embryology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C000589138:TCF7L2 protein, zebrafish; D058118:Transcription Factor 7-Like 2 Protein; D029961:Zebrafish Proteins