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The Journal of Neuroscience, November 26, 2008, 28(48):12887-12900; doi:10.1523/JNEUROSCI.2084-08.2008

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Development/Plasticity/Repair
A Crucial Role for Primary Cilia in Cortical Morphogenesis

Marc A. Willaredt,^1,2 Kerstin Hasenpusch-Theil,⁶ Humphrey A. R. Gardner,⁷ Igor Kitanovic,⁴ Vera C. Hirschfeld-Warneken,^3,5 Christian P. Gojak,^3,5 Karin Gorgas,² C. Lulu Bradford,¹ Joachim Spatz,^3,5 Stefan Wölfl,⁴ Thomas Theil,⁶ and Kerry L. Tucker^1,2

¹Interdisciplinary Center for Neurosciences, ²Department of Anatomy, ³Department of Biophysical Chemistry, Institute for Physical Chemistry, and ⁴Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany, ⁵Max Planck Institute for Metals Research, 70569 Stuttgart, Germany, ⁶Centres for Neuroscience Research and Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, and ⁷Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139

Correspondence should be addressed to Dr. Kerry L. Tucker, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany. Email: Kerry.Tucker{at}urz.uni-hd.de

Primary cilia are important sites of signal transduction involved in a wide range of developmental and postnatal functions. Proteolytic processing of the transcription factor Gli3, for example, occurs in primary cilia, and defects in intraflagellar transport (IFT), which is crucial for the maintenance of primary cilia, can lead to severe developmental defects and diseases. Here we report an essential role of primary cilia in forebrain development. Uncovered by N-ethyl-N-nitrosourea-mutagenesis, cobblestone is a hypomorphic allele of the IFT gene Ift88, in which Ift88 mRNA and protein levels are reduced by 70–80%. cobblestone mutants are distinguished by subpial heterotopias in the forebrain. Mutants show both severe defects in the formation of dorsomedial telencephalic structures, such as the choroid plexus, cortical hem and hippocampus, and also a relaxation of both dorsal-ventral and rostral-caudal compartmental boundaries. These defects phenocopy many of the abnormalities seen in the Gli3 mutant forebrain, and we show that Gli3 proteolytic processing is reduced, leading to an accumulation of the full-length activator isoform. In addition, we observe an upregulation of canonical Wnt signaling in the neocortex and in the caudal forebrain. Interestingly, the ultrastructure and morphology of ventricular cilia in the cobblestone mutants remains intact. Together, these results indicate a critical role for ciliary function in the developing forebrain.

Key words: primary cilia; cortex; Gli3; Wnt; Ift88; intraflagellar transport

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Received May 4, 2008; revised Aug. 8, 2008; accepted Oct. 15, 2008.

Correspondence should be addressed to Dr. Kerry L. Tucker, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany. Email: Kerry.Tucker{at}urz.uni-hd.de

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