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Curr Biol. 2014 Oct 6;24(19):2217-27. doi: 10.1016/j.cub.2014.08.006. Epub 2014 Sep 4.

Tcf7l2 is required for left-right asymmetric differentiation of habenular neurons.

Author information

1
Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Strasse 13-17, 68167 Mannheim, Germany.
2
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
3
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.
4
Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany.
5
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK; Neuroelectronics Research Flanders, 3001 Leuven, Belgium.
6
Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
7
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China.
8
Centre de Biologie du Développement (CDB), UPS, Université de Toulouse, 118 Route de Narbonne, 31062, France; CNRS, CDB UMR 5547, 31062 Toulouse, France.
9
Neuroelectronics Research Flanders, 3001 Leuven, Belgium; Vlaams Instituut voor Biotechnologie, 3001 Leuven, Belgium; KU Leuven, 3001 Leuven, Belgium.
10
Department of Molecular Evolution and Genomics, Centre for Organismal Studies (COS), Heidelberg University, Im Neuenheimer Feld 329, 69120 Heidelberg, Germany.
11
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.
12
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: s.wilson@ucl.ac.uk.
13
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.

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.

PMID:
25201686
PMCID:
PMC4194317
DOI:
10.1016/j.cub.2014.08.006
[Indexed for MEDLINE]
Free PMC Article

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