QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van de Water, S. Articles by Zivkovic, D. Search for Related Content PubMed PubMed Citation Articles by van de Water, S. Articles by Zivkovic, D.

Ectopic Wnt signal determines the eyeless phenotype of zebrafish masterblind mutant

Sandra van de Water¹, Marc van de Wetering², Jos Joore^1,, John Esseling^1,, Robert Bink, Hans Clevers² and Danica Zivkovic^1,*

¹ Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
² Department of Immunology, University Hospital, PO Box 85500, 3508 GA Utrecht, The Netherlands
Present address: Westburg b.v., PO Box 214, 3830 AE Leusden, The Netherlands
Present address: Laboratory of Plant Cell Biology, Arboretumlaan 4, 6703 BD Wageningen, The Netherlands

*Author for correspondence: dana{at}niob.knaw.nl

Accepted July 25, 2001

masterblind (mbl) is a zebrafish mutation characterised by the absence or reduction in size of the telencephalon, optic vesicles and olfactory placodes. We show that inhibition of Gsk3ß in zebrafish embryos either by overexpression of dominant negative dn gsk3ß mRNA or by lithium treatment after the midblastula transition phenocopies mbl. The loss of anterior neural tissue in mbl and lithium-treated embryos is preceded by posteriorization of presumptive anterior neuroectoderm during gastrulation, which is evident from the anterior shift of marker genes Otx2 and Wnt1. Heterozygous mbl embryos showed increased sensitivity to inhibition of GSK3ß by lithium or dn Xgsk3ß that led to the loss of eyes. Overexpression of gsk3ß mRNA rescued eyes and the wild-type fgf8 expression of homozygous mbl embryos. emx1 that delineates the telencephalon is expanded and shifted ventroanteriorly in mbl embryos. In contrast to fgf8, the emx1 expression domain was not restored upon overexpression of gsk3ß mRNA. These experiments place mbl as an antagonist of the Wnt pathway in parallel or upstream of the complex consisting of Axin, APC and Gsk3ß that binds and phosphorylates ß-catenin, thereby destabilising it. mbl maps on LG 3 close to a candidate gene axin1. In mbl we detected a point mutation in the conserved minimal Gsk3ß-binding domain of axin1 leading to a leucine to glutamine substitution at position 399. Overexpression of wild-type axin1 mRNA rescued mbl completely, demonstrating that mutant axin1 is responsible for the mutant phenotype. Overexpression of mutant L399Q axin1 in wild-type embryos resulted in a dose-dependent dominant negative activity as demonstrated by the loss of telencephalon and eyes. We suggest that the function of Axin1/Mbl protein is to antagonise the Wnt signal and in doing so to establish and maintain the most anterior CNS. Our findings provide new insights into the mechanisms by which the Wnt pathway generates anteroposterior polarity of the neural plate.

Key words: masterblind, zebrafish, Wnt, GSK3ß, lithium

This article has been cited by other articles:

				J. Ninkovic, C. Stigloher, C. Lillesaar, and L. Bally-Cuif Gsk3{beta}/PKA and Gli1 regulate the maintenance of neural progenitors at the midbrain-hindbrain boundary in concert with E(Spl) factor activity Development, September 15, 2008; 135(18): 3137 - 3148. [Abstract] [Full Text] [PDF]

				G. Davidson, B. Mao, I. del Barco Barrantes, and C. Niehrs Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning Development, March 14, 2003; 129(24): 5587 - 5596. [Abstract] [Full Text] [PDF]

				O. V. Lagutin, C. C. Zhu, D. Kobayashi, J. Topczewski, K. Shimamura, L. Puelles, H. R.C. Russell, P. J. McKinnon, L. Solnica-Krezel, and G. Oliver Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development Genes & Dev., February 1, 2003; 17(3): 368 - 379. [Abstract] [Full Text] [PDF]

				H. C. Korswagen, D. Y.M. Coudreuse, M. C. Betist, S. van de Water, D. Zivkovic, and H. C. Clevers The Axin-like protein PRY-1 is a negative regulator of a canonical Wnt pathway in C. elegans Genes & Dev., May 15, 2002; 16(10): 1291 - 1302. [Abstract] [Full Text] [PDF]

				M. Rallu, R. Machold, N. Gaiano, J. G. Corbin, A. P. McMahon, and G. Fishell Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling Development, January 11, 2002; 129(21): 4963 - 4974. [Abstract] [Full Text] [PDF]