The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling

• Published in: Cell reports (Cambridge) Vol. 39; no. 7; p. 110811
• Main Authors: Schembs, Leah, Willems, Ariane, Hasenpusch-Theil, Kerstin, Cooper, James D., Whiting, Katie, Burr, Karen, Bøstrand, Sunniva M.K., Selvaraj, Bhuvaneish T., Chandran, Siddharthan, Theil, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2022; Cell Press; Elsevier
• Subjects: Cilia - enzymology; Cilia - genetics; Cilia - metabolism; CP: Neuroscience; dorsal and ventral patterning; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; human cortex; Humans; INPP5E; Organoids - metabolism; Phosphoric Monoester Hydrolases - metabolism; primary cilia; sonic hedgehog; telencephalon; Telencephalon - enzymology; Telencephalon - metabolism; dorsal and ventral patterning; CP: Neuroscience; primary cilia; INPP5E; sonic hedgehog; telencephalon; human cortex
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110811

Defects in primary cilia, cellular antennas that control multiple intracellular signaling pathways, underlie several neurodevelopmental disorders, but it remains unknown how cilia control essential steps in human brain formation. Here, we show that cilia are present on the apical surface of radial glial cells in human fetal forebrain. Interfering with cilia signaling in human organoids by mutating the INPP5E gene leads to the formation of ventral telencephalic cell types instead of cortical progenitors and neurons. INPP5E mutant organoids also show increased Sonic hedgehog (SHH) signaling, and cyclopamine treatment partially rescues this ventralization. In addition, ciliary expression of SMO, GLI2, GPR161, and several intraflagellar transport (IFT) proteins is increased. Overall, these findings establish the importance of primary cilia for dorsal and ventral patterning in human corticogenesis, indicate a tissue-specific role of INPP5E as a negative regulator of SHH signaling, and have implications for the emerging roles of cilia in the pathogenesis of neurodevelopmental disorders. [Display omitted] •A mutation in the ciliary gene INPP5E leads to ventralization of cortical organoids•INPP5E mutant organoids show an up-regulation of SHH signaling•Inhibiting SHH signaling partially rescues the ventralization phenotype•INPP5E mutant primary cilia accumulate SMO, GPR161, and several IFT proteins Schembs et al. investigate the role of primary cilia in human corticogenesis using INPP5E mutant cerebral organoids. The analyses show that overactive SHH signaling causes the formation of ventral telencephalic progenitors and neurons instead of cortical cells and imply important ciliary functions in the pathogenesis of neurodevelopmental disorders.