A crucial role for primary cilia in cortical morphogenesis.
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.
Willaredt
Marc A
MA
Interdisciplinary Center for Neurosciences, Department of Anatomy, University of Heidelberg, 69120 Heidelberg, Germany.
Hasenpusch-Theil
Kerstin
K
Gardner
Humphrey A R
HA
Kitanovic
Igor
I
Hirschfeld-Warneken
Vera C
VC
Gojak
Christian P
CP
Gorgas
Karin
K
Bradford
C Lulu
CL
Spatz
Joachim
J
Wölfl
Stefan
S
Theil
Thomas
T
Tucker
Kerry L
KL
D000818:Animals; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism* / Q000648:ultrastructure; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D004805:Ependyma / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020547:Lateral Ventricles / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010447:Peptide Hydrolases / Q000378:metabolism; D016548:Prosencephalon / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D000074290:Zinc Finger Protein Gli3
C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D000074290:Zinc Finger Protein Gli3; D010447:Peptide Hydrolases