title: CPAP promotes timely cilium disassembly to maintain neural progenitor pool.
abstract: A mutation in the centrosomal-P4.1-associated protein (CPAP) causes Seckel syndrome with microcephaly, which is suggested to arise from a decline in neural progenitor cells (NPCs) during development. However, mechanisms ofNPCs maintenance remain unclear. Here, we report an unexpected role for the cilium inNPCs maintenance and identifyCPAPas a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly,CPAPprovides a scaffold for the cilium disassembly complex (CDC), which includes Nde1, Aurora A, andOFD1, recruited to the ciliary base for timely cilium disassembly. In contrast, mutatedCPAPfails to localize at the ciliary base associated with inefficientCDCrecruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re-entry leading to premature differentiation of patientiPS-derivedNPCs. AberrantCDCfunction also promotes premature differentiation ofNPCs in SeckeliPS-derived organoids. Thus, our results suggest a role for cilia in microcephaly and its involvement during neurogenesis and brain size control.
authors.affiliation: Center for Molecular Medicine and Institute for Biochemistry I of the University of Cologne, Cologne, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Gabriel
authors.affiliation: Center for Molecular Medicine and Institute for Biochemistry I of the University of Cologne, Cologne, Germany.
authors.forename: Arpit
authors.initials: A
authors.lastname: Wason
authors.affiliation: Center for Molecular Medicine and Institute for Biochemistry I of the University of Cologne, Cologne, Germany.
authors.forename: Anand
authors.initials: A
authors.lastname: Ramani
authors.affiliation: Center for Molecular Medicine and Institute for Biochemistry I of the University of Cologne, Cologne, Germany.
authors.forename: Li Ming
authors.initials: LM
authors.lastname: Gooi
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Keller
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Andrei
authors.initials: A
authors.lastname: Pozniakovsky
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Poser
authors.affiliation: DFG-Research Center and Cluster of Excellence for Regenerative Therapies, TU-Dresden, Dresden, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Noack
authors.affiliation: Center for Physiology and Pathophysiology, Institute for Neurophysiology Medical Faculty University of Cologne, Cologne, Germany.
authors.forename: Narasimha Swamy
authors.initials: NS
authors.lastname: Telugu
authors.affiliation: DFG-Research Center and Cluster of Excellence for Regenerative Therapies, TU-Dresden, Dresden, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Calegari
authors.affiliation: Center for Physiology and Pathophysiology, Institute for Neurophysiology Medical Faculty University of Cologne, Cologne, Germany.
authors.forename: Tomo
authors.initials: T
authors.lastname: Šarić
authors.affiliation: Center for Physiology and Pathophysiology, Institute for Neurophysiology Medical Faculty University of Cologne, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Hyman
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardo
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Callaini
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center Alfasial University, Riyadh, Saudi Arabia Department of Anatomy and Cell Biology, College of Medicine Alfasial University, Riyadh, Saudi Arabia.
authors.forename: Fowzan Sami
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: Center for Molecular Medicine and Institute for Biochemistry I of the University of Cologne, Cologne, Germany jay.gopalakrishnan@uni-koeln.de.
authors.forename: Jay
authors.initials: J
authors.lastname: Gopalakrishnan
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002923:Cilia / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology; D008831:Microcephaly / Q000235:genetics / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D013577:Syndrome
chemical_list: C414735:CENPJ protein, human; D008869:Microtubule-Associated Proteins; C525094:Nde1 protein, human; C115130:OFD1 protein, human; D011506:Proteins; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: CPAP; brain organoids; cilium; microcephaly; neural progenitor cell maintenance