The Essential Role of Centrosomal NDE1 in Human Cerebral Cortex Neurogenesis

• Published in: American journal of human genetics Vol. 88; no. 5; pp. 523 - 535
• Main Authors: Bakircioglu, Mehmet, Carvalho, Ofélia P., Khurshid, Maryam, Cox, James J., Tuysuz, Beyhan, Barak, Tanyeri, Yilmaz, Saliha, Caglayan, Okay, Dincer, Alp, Nicholas, Adeline K., Quarrell, Oliver, Springell, Kelly, Karbani, Gulshan, Malik, Saghira, Gannon, Caroline, Sheridan, Eamonn, Crosier, Moira, Lisgo, Steve N., Lindsay, Susan, Bilguvar, Kaya, Gergely, Fanni, Gunel, Murat, Woods, C. Geoffrey
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.05.2011; Cell Press; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain; Cell Cycle Proteins - genetics; Cells; Centrosome - metabolism; Centrosomes; Cerebral Cortex - embryology; Cerebral Cortex - growth & development; Child, Preschool; Cortex; Data processing; DNA Mutational Analysis; Embryos; Epithelial Cells - metabolism; Exons; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic disorders; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; HeLa Cells; Homozygote; Humans; Infant; Intellectual disabilities; Lamination; Male; Medical genetics; Medical sciences; Mental retardation; Mice; Microcephaly - genetics; Microencephaly; Microtubule-Associated Proteins - genetics; Molecular and cellular biology; Mutation; Neural stem cells; Neural Stem Cells - metabolism; Neurogenesis; Neurons; Phenotype; Pregnancy; Progeny; RNA, Messenger - genetics; RNA, Messenger - metabolism; Spindles; Standard deviation; Transfection; Human; Genetics; Cerebral cortex; Essential; Centrosome
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.03.019

We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (≤10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.