The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor

Abstract : Agenesis of the corpus callosum (AgCC) is a frequent brain disorder found in over 80 human congenital syndromes including ciliopathies. Here, we report a severe AgCC in Ftm/Rpgrip1l knockout mouse, which provides a valuable model for Meckel–Grüber syndrome. Rpgrip1l encodes a protein of the ciliary transition zone, which is essential for ciliogenesis in several cell types in mouse including neuroepithelial cells in the developing forebrain. We show that AgCC in Rpgrip1l−/– mouse is associated with a disturbed location of guidepost cells in the dorsomedial telencephalon. This mislocalization results from early patterning defects and abnormal cortico-septal boundary (CSB) formation in the medial telencephalon. We demonstrate that all these defects primarily result from altered GLI3 processing. Indeed, AgCC, together with patterning defects and mispositioning of guidepost cells, is rescued by overexpressing in Rpgrip1l−/− embryos, the short repressor form of the GLI3 transcription factor (GLI3R), provided by the Gli3Δ699 allele. Furthermore, Gli3Δ699 also rescues AgCC in Rfx3−/− embryos deficient for the ciliogenic RFX3 transcription factor that regulates the expression of several ciliary genes. These data demonstrate that GLI3 processing is a major outcome of primary cilia function in dorsal telencephalon morphogenesis. Rescuing CC formation in two independent ciliary mutants by GLI3Δ699 highlights the crucial role of primary cilia in maintaining the proper level of GLI3R required for morphogenesis of the CC.
Type de document :
Article dans une revue
Human Molecular Genetics, Oxford University Press (OUP), 2015, 24 (17), pp.4997 - 5014. 〈10.1093/hmg/ddv221〉
Liste complète des métadonnées

http://hal.upmc.fr/hal-01537450
Contributeur : Gestionnaire Hal-Upmc <>
Soumis le : lundi 12 juin 2017 - 15:45:40
Dernière modification le : vendredi 9 février 2018 - 16:24:49

Lien texte intégral

Identifiants

Collections

Citation

Christine Laclef, Isabelle Anselme, Laurianne Besse, Martin Catala, Aurélien Palmyre, et al.. The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor. Human Molecular Genetics, Oxford University Press (OUP), 2015, 24 (17), pp.4997 - 5014. 〈10.1093/hmg/ddv221〉. 〈hal-01537450〉

Partager

Métriques

Consultations de la notice

41