title: The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Center for Human Genetics and Genomics, and Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Bakircioglu
authors.forename: Ofélia P
authors.initials: OP
authors.lastname: Carvalho
authors.forename: Maryam
authors.initials: M
authors.lastname: Khurshid
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tuysuz
authors.forename: Tanyeri
authors.initials: T
authors.lastname: Barak
authors.forename: Saliha
authors.initials: S
authors.lastname: Yilmaz
authors.forename: Okay
authors.initials: O
authors.lastname: Caglayan
authors.forename: Alp
authors.initials: A
authors.lastname: Dincer
authors.forename: Adeline K
authors.initials: AK
authors.lastname: Nicholas
authors.forename: Oliver
authors.initials: O
authors.lastname: Quarrell
authors.forename: Kelly
authors.initials: K
authors.lastname: Springell
authors.forename: Gulshan
authors.initials: G
authors.lastname: Karbani
authors.forename: Saghira
authors.initials: S
authors.lastname: Malik
authors.forename: Caroline
authors.initials: C
authors.lastname: Gannon
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.forename: Moira
authors.initials: M
authors.lastname: Crosier
authors.forename: Steve N
authors.initials: SN
authors.lastname: Lisgo
authors.forename: Susan
authors.initials: S
authors.lastname: Lindsay
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.forename: Fanni
authors.initials: F
authors.lastname: Gergely
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D018385:Centrosome / Q000378:metabolism*; D002540:Cerebral Cortex / Q000196:embryology* / Q000254:growth & development; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004847:Epithelial Cells / Q000378:metabolism; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons; D010641:Phenotype; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; C525094:Nde1 protein, human; C531336:Nde1 protein, mouse; D012333:RNA, Messenger