The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling
Leah Schembs,
Ariane Willems,
Kerstin Hasenpusch-Theil,
James D. Cooper,
Katie Whiting,
Karen Burr,
Sunniva M.K. Bøstrand,
Bhuvaneish T. Selvaraj,
Siddharthan Chandran,
Thomas Theil
Affiliations
Leah Schembs
Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, UK
Ariane Willems
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh EH16 4SB, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK
Kerstin Hasenpusch-Theil
Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK
James D. Cooper
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh EH16 4SB, UK
Katie Whiting
Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, UK
Karen Burr
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh EH16 4SB, UK
Sunniva M.K. Bøstrand
Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, UK
Bhuvaneish T. Selvaraj
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh EH16 4SB, UK; Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh EH16 4SB, UK
Siddharthan Chandran
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh EH16 4SB, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh EH16 4SB, UK
Thomas Theil
Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, UK; Corresponding author
Summary: 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.
