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Annual Review of Genomics and Human Genetics

Volume 19, 2018

The Genetics of Primary Microcephaly

Abstract

Primary microcephaly (MCPH, for “microcephaly primary hereditary”) is a disorder of brain development that results in a head circumference more than 3 standard deviations below the mean for age and gender. It has a wide variety of causes, including toxic exposures, in utero infections, and metabolic conditions. While the genetic microcephaly syndromes are relatively rare, studying these syndromes can reveal molecular mechanisms that are critical in the regulation of neural progenitor cells, brain size, and human brain evolution. Many of the causative genes for MCPH encode centrosomal proteins involved in centriole biogenesis. However, other MCPH genes fall under different mechanistic categories, notably DNA replication and repair. Recent gene discoveries and functional studies have implicated novel cellular processes, such as cytokinesis, centromere and kinetochore function, transmembrane or intracellular transport, Wnt signaling, and autophagy, as well as the apical polarity complex. Thus, MCPH genes implicate a wide variety of molecular and cellular mechanisms in the regulation of cerebral cortical size during development.

Keyword(s): centrosome, DNA repair, microcephaly, radial glial cells
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2018-08-31
2024-04-18
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Literature Cited

  1. 1.  Al-Dosari MS, Shaheen R, Colak D, Alkuraya FS 2010. Novel CENPJ mutation causes Seckel syndrome. J. Med. Genet. 47:411–14
     [Google Scholar]
  2. 2.  Alakbarzade V, Hameed A, Quek DQ, Chioza BA, Baple EL et al. 2015. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat. Genet. 47:814–17
     [Google Scholar]
  3. 3.  Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H et al. 2006. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nat. Cell Biol. 8:725–33
     [Google Scholar]
  4. 4.  Alkuraya FS, Cai X, Emery C, Mochida GH, Al-Dosari MS et al. 2011. Human mutations in NDE1 cause extreme microcephaly with lissencephaly. Am. J. Hum. Genet. 88:536–47
     [Google Scholar]
  5. 5.  Anderson CT, Stearns T 2009. Centriole age underlies asynchronous primary cilium growth in mammalian cells. Curr. Biol. 19:1498–502
     [Google Scholar]
  6. 6.  Anderson SA, Eisenstat DD, Shi L, Rubenstein JL 1997. Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science 278:474–76
     [Google Scholar]
  7. 7.  Angevine JB Jr., Sidman RL 1961. Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature 192:766–68
     [Google Scholar]
  8. 8.  Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis JD 2005. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45:207–21
     [Google Scholar]
  9. 9.  Atwood SX, Li M, Lee A, Tang JY, Oro AE 2013. GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas. Nature 494:484–88
     [Google Scholar]
  10. 10.  Awad S, Al-Dosari MS, Al-Yacoub N, Colak D, Salih MA et al. 2013. Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum. Mol. Genet. 22:2200–13
     [Google Scholar]
  11. 11.  Bae BI, Jayaraman D, Walsh CA 2015. Genetic changes shaping the human brain. Dev. Cell 32:423–34
     [Google Scholar]
  12. 12.  Bakircioglu M, Carvalho OP, Khurshid M, Cox JJ, Tuysuz B et al. 2011. The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. Am. J. Hum. Genet. 88:523–35
     [Google Scholar]
  13. 13.  Barnes DE, Stamp G, Rosewell I, Denzel A, Lindahl T 1998. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr. Biol. 8:1395–98
     [Google Scholar]
  14. 14.  Bazzi H, Anderson KV 2014. Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo. PNAS 111:E1491–500
     [Google Scholar]
  15. 15.  Betizeau M, Cortay V, Patti D, Pfister S, Gautier E et al. 2013. Precursor diversity and complexity of lineage relationships in the outer subventricular zone of the primate. Neuron 80:442–57
     [Google Scholar]
  16. 16.  Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J et al. 2011. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat. Genet. 43:356–59
     [Google Scholar]
  17. 17.  Bicknell LS, Walker S, Klingseisen A, Stiff T, Leitch A et al. 2011. Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat. Genet. 43:350–55
     [Google Scholar]
  18. 18.  Bilguvar K, Ozturk AK, Louvi A, Kwan KY, Choi M et al. 2010. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467:207–10
     [Google Scholar]
  19. 19.  Blachon S, Gopalakrishnan J, Omori Y, Polyanovsky A, Church A et al. 2008. Drosophila asterless and vertebrate Cep152 are orthologs essential for centriole duplication. Genetics 180:2081–94
     [Google Scholar]
  20. 20.  Bogoyevitch MA, Yeap YY, Qu Z, Ngoei KR, Yip YY et al. 2012. WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression. J. Cell Sci. 125:5096–109
     [Google Scholar]
  21. 21.  Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S et al. 2002. ASPM is a major determinant of cerebral cortical size. Nat. Genet. 32:316–20
     [Google Scholar]
  22. 22.  Bond J, Roberts E, Springell K, Lizarraga SB, Scott S et al. 2005. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat. Genet. 37:353–55
     [Google Scholar]
  23. 23.  Bond J, Woods CG 2006. Cytoskeletal genes regulating brain size. Curr. Opin. Cell Biol. 18:95–101
     [Google Scholar]
  24. 24.  Bornens M 2012. The centrosome in cells and organisms. Science 335:422–26
     [Google Scholar]
  25. 25.  Brown NJ, Marjanović M, Lüders J, Stracker TH, Costanzo V 2013. Cep63 and Cep152 cooperate to ensure centriole duplication. PLOS ONE 8:e69986
     [Google Scholar]
  26. 26.  Buchman JJ, Durak O, Tsai LH 2011. ASPM regulates Wnt signaling pathway activity in the developing brain. Genes Dev 25:1909–14
     [Google Scholar]
  27. 27.  Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC et al. 2006. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124:287–99
     [Google Scholar]
  28. 28.  Burrage LC, Charng WL, Eldomery MK, Willer JR, Davis EE et al. 2015. De novo GMNN mutations cause autosomal-dominant primordial dwarfism associated with Meier-Gorlin syndrome. Am. J. Hum. Genet. 97:904–13
     [Google Scholar]
  29. 29.  Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M et al. 1998. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–86
     [Google Scholar]
  30. 30.  Chae TH, Walsh CA 2007. Genes that control the size of the cerebral cortex. Novartis Found. Symp. 288:79–90
     [Google Scholar]
  31. 31.  Chan CH, Godinho LN, Thomaidou D, Tan SS, Gulisano M, Parnavelas JG 2001. Emx1 is a marker for pyramidal neurons of the cerebral cortex. Cereb. Cortex 11:1191–98
     [Google Scholar]
  32. 32.  Chenn A, McConnell SK 1995. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82:631–41
     [Google Scholar]
  33. 33.  Chenn A, Walsh CA 2002. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365–69
     [Google Scholar]
  34. 34.  Dauber A, Lafranchi SH, Maliga Z, Lui JC, Moon JE et al. 2012. Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein Ninein. J. Clin. Endocrinol. Metab. 97:E2140–51
     [Google Scholar]
  35. 35.  de Carlos JA, López-Mascaraque L, Valverde F 1996. Dynamics of cell migration from the lateral ganglionic eminence in the rat. J. Neurosci. 16:6146–56
     [Google Scholar]
  36. 36.  Deans B, Griffin CS, Maconochie M, Thacker J 2000. Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. EMBO J 19:6675–85
     [Google Scholar]
  37. 37.  do Carmo Avides M, Glover DM 1999. Abnormal spindle protein, Asp, and the integrity of mitotic centrosomal microtubule organizing centers. Science 283:1733–35
     [Google Scholar]
  38. 38.  do Carmo Avides M, Tavares A, Glover DM 2001. Polo kinase and Asp are needed to promote the mitotic organizing activity of centrosomes. Nat. Cell Biol. 3:421–24
     [Google Scholar]
  39. 39.  Dobyns WB 2002. Primary microcephaly: new approaches for an old disorder. Am. J. Med. Genet. 112:315–17
     [Google Scholar]
  40. 40.  Doxsey SJ, Stein P, Evans L, Calarco PD, Kirschner M 1994. Pericentrin, a highly conserved centrosome protein involved in microtubule organization. Cell 76:639–50
     [Google Scholar]
  41. 41.  Dzhindzhev NS, Yu QD, Weiskopf K, Tzolovsky G, Cunha-Ferreira I et al. 2010. Asterless is a scaffold for the onset of centriole assembly. Nature 467:714–18
     [Google Scholar]
  42. 42.  Evrony GD, Cordero DR, Shen J, Partlow JN, Yu TW et al. 2017. Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome. Genome Res 27:1323–35
     [Google Scholar]
  43. 43.  Faheem M, Naseer MI, Rasool M, Chaudhary AG, Kumosani TA et al. 2015. Molecular genetics of human primary microcephaly: an overview. BMC Med. Genom. 8:Suppl. 1S4
     [Google Scholar]
  44. 44.  Farkas LM, Huttner WB 2008. The cell biology of neural stem and progenitor cells and its significance for their proliferation versus differentiation during mammalian brain development. Curr. Opin. Cell Biol. 20:707–15
     [Google Scholar]
  45. 45.  Feng Y, Walsh CA 2004. Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron 44:279–93
     [Google Scholar]
  46. 46.  Fenwick AL, Kliszczak M, Cooper F, Murray J, Sanchez-Pulido L et al. 2016. Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. Am. J. Hum. Genet. 99:125–38
     [Google Scholar]
  47. 47.  Fietz SA, Kelava I, Vogt J, Wilsch-Brauninger M, Stenzel D et al. 2010. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat. Neurosci. 13:690–99
     [Google Scholar]
  48. 48.  Fish JL, Kosodo Y, Enard W, Pääbo S, Huttner WB 2006. Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. PNAS 103:10438–43
     [Google Scholar]
  49. 49.  Franco SJ, Gil-Sanz C, Martinez-Garay I, Espinosa A, Harkins-Perry SR et al. 2012. Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 337:746–49
     [Google Scholar]
  50. 50.  Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA et al. 1998. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396:173–77
     [Google Scholar]
  51. 51.  Frise E, Knoblich JA, Younger-Shepherd S, Jan LY, Jan YN 1996. The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. PNAS 93:11925–32
     [Google Scholar]
  52. 52.  Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y et al. 1998. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95:891–902
     [Google Scholar]
  53. 53.  Garcia-Gonzalo FR, Reiter JF 2012. Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access. J. Cell Biol. 197:697–709
     [Google Scholar]
  54. 54.  García-Moreno F, Vasistha NA, Trevia N, Bourne JA, Molnár Z 2012. Compartmentalization of cerebral cortical germinal zones in a lissencephalic primate and gyrencephalic rodent. Cereb. Cortex 22:482–92
     [Google Scholar]
  55. 55.  Genin A, Desir J, Lambert N, Biervliet M, Van Der Aa N et al. 2012. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum. Mol. Genet. 21:5306–17
     [Google Scholar]
  56. 56.  Gilmore EC, Walsh CA 2013. Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdiscip. Rev. Dev. Biol. 2:461–78
     [Google Scholar]
  57. 57.  Gonczy P 2012. Towards a molecular architecture of centriole assembly. Nat. Rev. Mol. Cell Biol. 13:425–35
     [Google Scholar]
  58. 58.  Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR 2002. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J. Neurosci. 22:6309–14
     [Google Scholar]
  59. 59.  Gu Y, Sekiguchi J, Gao Y, Dikkes P, Frank K et al. 2000. Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. PNAS 97:2668–73
     [Google Scholar]
  60. 60.  Guarguaglini G, Duncan PI, Stierhof YD, Holmstrom T, Duensing S, Nigg EA 2005. The forkhead-associated domain protein Cep170 interacts with Polo-like kinase 1 and serves as a marker for mature centrioles. Mol. Biol. Cell 16:1095–107
     [Google Scholar]
  61. 61.  Guemez-Gamboa A, Nguyen LN, Yang H, Zaki MS, Kara M et al. 2015. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat. Genet. 47:809–13
     [Google Scholar]
  62. 62.  Guernsey DL, Jiang H, Hussin J, Arnold M, Bouyakdan K et al. 2010. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am. J. Hum. Genet. 87:40–51
     [Google Scholar]
  63. 63.  Guernsey DL, Matsuoka M, Jiang H, Evans S, Macgillivray C et al. 2011. Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome. Nat. Genet. 43:360–64
     [Google Scholar]
  64. 64.  Guo C, Eckler MJ, McKenna WL, McKinsey GL, Rubenstein JL, Chen B 2013. Fezf2 expression identifies a multipotent progenitor for neocortical projection neurons, astrocytes, and oligodendrocytes. Neuron 80:1167–74
     [Google Scholar]
  65. 65.  Hammerle B, Vera-Samper E, Speicher S, Arencibia R, Martinez S, Tejedor FJ 2002. Mnb/Dyrk1A is transiently expressed and asymmetrically segregated in neural progenitor cells at the transition to neurogenic divisions. Dev. Biol. 246:259–73
     [Google Scholar]
  66. 66.  Hansen DV, Lui JH, Parker PR, Kriegstein AR 2010. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464:554–61
     [Google Scholar]
  67. 67.  Harding BN, Moccia A, Drunat S, Soukarieh O, Tubeuf H et al. 2016. Mutations in citron kinase cause recessive microlissencephaly with multinucleated neurons. Am. J. Hum. Genet. 99:511–20
     [Google Scholar]
  68. 68.  Harley ME, Murina O, Leitch A, Higgs MR, Bicknell LS et al. 2016. TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. Nat. Genet. 48:36–43
     [Google Scholar]
  69. 69.  Hatanaka Y, Murakami F 2002. In vitro analysis of the origin, migratory behavior, and maturation of cortical pyramidal cells. J. Comp. Neurol. 454:1–14
     [Google Scholar]
  70. 70.  Hatch EM, Kulukian A, Holland AJ, Cleveland DW, Stearns T 2010. Cep152 interacts with Plk4 and is required for centriole duplication. J. Cell Biol. 191:721–29
     [Google Scholar]
  71. 71.  Haydar TF, Ang E Jr., Rakic P 2003. Mitotic spindle rotation and mode of cell division in the developing telencephalon. PNAS 100:2890–95
     [Google Scholar]
  72. 72.  Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M et al. 2001. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29:353–66
     [Google Scholar]
  73. 73.  Higgins J, Midgley C, Bergh AM, Bell SM, Askham JM et al. 2010. Human ASPM participates in spindle organisation, spindle orientation and cytokinesis. BMC Cell Biol 11:85
     [Google Scholar]
  74. 74.  Hu WF, Pomp O, Ben-Omran T, Kodani A, Henke K et al. 2014. Katanin p80 regulates human cortical development by limiting centriole and cilia number. Neuron 84:1240–57
     [Google Scholar]
  75. 75.  Hussain MS, Baig SM, Neumann S, Nurnberg G, Farooq M et al. 2012. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am. J. Hum. Genet. 90:871–78
     [Google Scholar]
  76. 76.  Hussain MS, Baig SM, Neumann S, Peche VS, Szczepanski S et al. 2013. CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. Hum. Mol. Genet. 22:5199–214
     [Google Scholar]
  77. 77.  Hutchins JR, Toyoda Y, Hegemann B, Poser I, Heriche JK et al. 2010. Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science 328:593–99
     [Google Scholar]
  78. 78.  Inaba M, Venkei ZG, Yamashita YM 2015. The polarity protein Baz forms a platform for the centrosome orientation during asymmetric stem cell division in the Drosophila male germline. eLife 4:e04960
     [Google Scholar]
  79. 79.  Insolera R, Bazzi H, Shao W, Anderson KV, Shi SH 2014. Cortical neurogenesis in the absence of centrioles. Nat. Neurosci. 17:1528–35
     [Google Scholar]
  80. 80.  Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C et al. 2002. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am. J. Hum. Genet. 71:136–42
     [Google Scholar]
  81. 81.  Jayaraman D, Kodani A, Gonzalez DM, Mancias JD, Mochida GH et al. 2016. Microcephaly proteins Wdr62 and Aspm define a mother centriole complex regulating centriole biogenesis, apical complex, and cell fate. Neuron 92:813–28
     [Google Scholar]
  82. 82.  Juschke C, Xie Y, Postiglione MP, Knoblich JA 2014. Analysis and modeling of mitotic spindle orientations in three dimensions. PNAS 111:1014–19
     [Google Scholar]
  83. 83.  Kadir R, Harel T, Markus B, Perez Y, Bakhrat A et al. 2016. ALFY-controlled DVL3 autophagy regulates Wnt signaling, determining human brain size. PLOS Genet 12:e1005919
     [Google Scholar]
  84. 84.  Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E et al. 2011. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat. Genet. 43:23–26
     [Google Scholar]
  85. 85.  Kelava I, Reillo I, Murayama AY, Kalinka AT, Stenzel D et al. 2012. Abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus. Cereb. . Cortex 22:469–81
     [Google Scholar]
  86. 86.  Khan MA, Rupp VM, Orpinell M, Hussain MS, Altmüller J et al. 2014. A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family. Hum. Mol. Genet. 23:5940–49
     [Google Scholar]
  87. 87.  Kim S, Lehtinen MK, Sessa A, Zappaterra MW, Cho SH et al. 2010. The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron 66:69–84
     [Google Scholar]
  88. 88.  Kim S, Zaghloul NA, Bubenshchikova E, Oh EC, Rankin S et al. 2011. Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry. Nat. Cell Biol. 13:351–60
     [Google Scholar]
  89. 89.  Klingseisen A, Jackson AP 2011. Mechanisms and pathways of growth failure in primordial dwarfism. Genes Dev 25:2011–24
     [Google Scholar]
  90. 90.  Knoblich JA, Jan LY, Jan YN 1995. Asymmetric segregation of Numb and Prospero during cell division. Nature 377:624–27
     [Google Scholar]
  91. 91.  Kobayashi T, Dynlacht BD 2011. Regulating the transition from centriole to basal body. J. Cell Biol. 193:435–44
     [Google Scholar]
  92. 92.  Kodani A, Salome Sirerol-Piquer M, Seol A, Garcia-Verdugo JM, Reiter JF 2013. Kif3a interacts with Dynactin subunit p150Glued to organize centriole subdistal appendages. EMBO J 32:597–607
     [Google Scholar]
  93. 93.  Kodani A, Tonthat V, Wu B, Sütterlin C 2010. Par6α interacts with the dynactin subunit p150Glued and is a critical regulator of centrosomal protein recruitment. Mol. Biol. Cell 21:3376–85
     [Google Scholar]
  94. 94.  Kodani A, Yu TW, Johnson JR, Jayaraman D, Johnson TL et al. 2015. Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. eLife 4:e07519
     [Google Scholar]
  95. 95.  Kohlmaier G, Loncarek J, Meng X, McEwen BF, Mogensen MM et al. 2009. Overly long centrioles and defective cell division upon excess of the SAS-4-related protein CPAP. Curr. Biol. 19:1012–18
     [Google Scholar]
  96. 96.  Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J et al. 2003. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am. J. Hum. Genet. 72:1359–69
     [Google Scholar]
  97. 97.  Konno D, Shioi G, Shitamukai A, Mori A, Kiyonari H et al. 2008. Neuroepithelial progenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis. Nat. Cell Biol. 10:93–101
     [Google Scholar]
  98. 98.  Kosodo Y, Roper K, Haubensak W, Marzesco AM, Corbeil D, Huttner WB 2004. Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J 23:2314–24
     [Google Scholar]
  99. 99.  Kumar A, Girimaji SC, Duvvari MR, Blanton SH 2009. Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am. J. Hum. Genet. 84:286–90
     [Google Scholar]
  100. 100.  Lane HA, Nigg EA 1996. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J. Cell Biol. 135:1701–13
     [Google Scholar]
  101. 101.  Lavdas AA, Grigoriou M, Pachnis V, Parnavelas JG 1999. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J. Neurosci. 19:7881–88
     [Google Scholar]
  102. 102.  Lehtinen MK, Zappaterra MW, Chen X, Yang YJ, Hill AD et al. 2011. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69:893–905
     [Google Scholar]
  103. 103.  Leid M, Ishmael JE, Avram D, Shepherd D, Fraulob V, Dolle P 2004. CTIP1 and CTIP2 are differentially expressed during mouse embryogenesis. Gene Expr. Patterns 4:733–39
     [Google Scholar]
  104. 104.  Li H, Bielas SL, Zaki MS, Ismail S, Farfara D et al. 2016. Biallelic mutations in citron kinase link mitotic cytokinesis to human primary microcephaly. Am. J. Hum. Genet. 99:501–10
     [Google Scholar]
  105. 105.  Lin SY, Rai R, Li K, Xu ZX, Elledge SJ 2005. BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly. PNAS 102:15105–9
     [Google Scholar]
  106. 106.  Lin YC, Chang CW, Hsu WB, Tang CJ, Lin YN et al. 2013. Human microcephaly protein CEP135 binds to hSAS-6 and CPAP, and is required for centriole assembly. EMBO J 32:1141–54
     [Google Scholar]
  107. 107.  Lizarraga SB, Margossian SP, Harris MH, Campagna DR, Han AP et al. 2010. Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors. Development 137:1907–17
     [Google Scholar]
  108. 108.  Lui JH, Hansen DV, Kriegstein AR 2011. Development and evolution of the human neocortex. Cell 146:18–36
     [Google Scholar]
  109. 109.  Major MB, Roberts BS, Berndt JD, Marine S, Anastas J et al. 2008. New regulators of Wnt/β-catenin signaling revealed by integrative molecular screening. Sci. Signal. 1:ra12
     [Google Scholar]
  110. 110.  Marin-Padilla M 1998. Cajal-Retzius cells and the development of the neocortex. Trends Neurosci 21:64–71
     [Google Scholar]
  111. 111.  Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS et al. 2014. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat. Genet. 46:1283–92
     [Google Scholar]
  112. 112.  Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S et al. 1998. Positional cloning of the gene for Nijmegen breakage syndrome. Nat. Genet. 19:179–81
     [Google Scholar]
  113. 113.  McEvilly RJ, de Diaz MO, Schonemann MD, Hooshmand F, Rosenfeld MG 2002. Transcriptional regulation of cortical neuron migration by POU domain factors. Science 295:1528–32
     [Google Scholar]
  114. 114.  Megraw TL, Sharkey JT, Nowakowski RS 2011. Cdk5rap2 exposes the centrosomal root of microcephaly syndromes. Trends Cell Biol 21:470–80
     [Google Scholar]
  115. 115.  Mirzaa GM, Vitre B, Carpenter G, Abramowicz I, Gleeson JG et al. 2014. Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum. Genet. 133:1023–39
     [Google Scholar]
  116. 116.  Mishra-Gorur K, Caglayan AO, Schaffer AE, Chabu C, Henegariu O et al. 2014. Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors. Neuron 84:1226–39
     [Google Scholar]
  117. 117.  Miyamoto T, Akutsu SN, Fukumitsu A, Morino H, Masatsuna Y et al. 2017. PLK1-mediated phosphorylation of WDR62/MCPH2 ensures proper mitotic spindle orientation. Hum. Mol. Genet. 26:4429–40
     [Google Scholar]
  118. 118.  Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N et al. 2017. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann. Neurol. 82:562–77
     [Google Scholar]
  119. 119.  Mochida GH, Ganesh VS, de Michelena MI, Dias H, Atabay KD et al. 2012. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat. Genet. 44:1260–64
     [Google Scholar]
  120. 120.  Mochida GH, Mahajnah M, Hill AD, Basel-Vanagaite L, Gleason D et al. 2009. A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am. J. Hum. Genet. 85:897–902
     [Google Scholar]
  121. 121.  Mochida GH, Rajab A, Eyaid W, Lu A, Al-Nouri D et al. 2004. Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J. Med. Genet. 41:e87
     [Google Scholar]
  122. 122.  Montgomery SH, Mundy NI 2014. Microcephaly genes evolved adaptively throughout the evolution of eutherian mammals. BMC Evol. Biol. 14:120
     [Google Scholar]
  123. 123.  Morrison SJ, Kimble J 2006. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441:1068–74
     [Google Scholar]
  124. 124.  Nakayama T, Al-Maawali A, El-Quessny M, Rajab A, Khalil S et al. 2015. Mutations in PYCR2, encoding pyrroline-5-carboxylate reductase 2, cause microcephaly and hypomyelination. Am. J. Hum. Genet. 96:709–19
     [Google Scholar]
  125. 125.  Nakayama T, Wu J, Galvin-Parton P, Weiss J, Andriola MR et al. 2017. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum. Mutat. 38:1348–54
     [Google Scholar]
  126. 126.  Nicholas AK, Khurshid M, Desir J, Carvalho OP, Cox JJ et al. 2010. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat. Genet. 42:1010–14
     [Google Scholar]
  127. 127.  Nieto M, Monuki ES, Tang H, Imitola J, Haubst N et al. 2004. Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex. J. Comp. Neurol. 479:168–80
     [Google Scholar]
  128. 128.  Nigg EA, Raff JW 2009. Centrioles, centrosomes, and cilia in health and disease. Cell 139:663–78
     [Google Scholar]
  129. 129.  Nigg EA, Stearns T 2011. The centrosome cycle: centriole biogenesis, duplication and inherent asymmetries. Nat. Cell Biol. 13:1154–60
     [Google Scholar]
  130. 130.  Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR 2001. Neurons derived from radial glial cells establish radial units in neocortex. Nature 409:714–20
     [Google Scholar]
  131. 131.  Noctor SC, Flint AC, Weissman TA, Wong WS, Clinton BK, Kriegstein AR 2002. Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J. Neurosci. 22:3161–73
     [Google Scholar]
  132. 132.  Noctor SC, Martínez-Cerdeño V, Ivic L, Kriegstein AR 2004. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7:136–44
     [Google Scholar]
  133. 133.  Noctor SC, Martínez-Cerdeño V, Kriegstein AR 2008. Distinct behaviors of neural stem and progenitor cells underlie cortical neurogenesis. J. Comp. Neurol. 508:28–44
     [Google Scholar]
  134. 134.  O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M et al. 2001. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol. Cell 8:1175–85
     [Google Scholar]
  135. 135.  O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA 2003. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat. Genet. 33:497–501
     [Google Scholar]
  136. 136.  Ohkura H, Hagan IM, Glover DM 1995. The conserved Schizosaccharomyces pombe kinase plo1, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells. Genes Dev 9:1059–73
     [Google Scholar]
  137. 137.  Orii KE, Lee Y, Kondo N, McKinnon PJ 2006. Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. PNAS 103:10017–22
     [Google Scholar]
  138. 138.  Paramasivam M, Chang YJ, LoTurco JJ 2007. ASPM and citron kinase co-localize to the midbody ring during cytokinesis. Cell Cycle 6:1605–12
     [Google Scholar]
  139. 139.  Paridaen JT, Huttner WB 2014. Neurogenesis during development of the vertebrate central nervous system. EMBO Rep 15:351–64
     [Google Scholar]
  140. 140.  Paridaen JT, Wilsch-Brauninger M, Huttner WB 2013. Asymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division. Cell 155:333–44
     [Google Scholar]
  141. 141.  Passemard S, Titomanlio L, Elmaleh M, Afenjar A, Alessandri JL et al. 2009. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology 73:962–69
     [Google Scholar]
  142. 142.  Payne F, Colnaghi R, Rocha N, Seth A, Harris J et al. 2014. Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance. J. Clin. Investig. 124:4028–38
     [Google Scholar]
  143. 143.  Peyre E, Jaouen F, Saadaoui M, Haren L, Merdes A et al. 2011. A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells. J. Cell Biol. 193:141–54
     [Google Scholar]
  144. 144.  Pulvers JN, Bryk J, Fish JL, Wilsch-Brauninger M, Arai Y et al. 2010. Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline. PNAS 107:16595–600
     [Google Scholar]
  145. 145.  Qian YW, Erikson E, Li C, Maller JL 1998. Activated polo-like kinase Plx1 is required at multiple points during mitosis in Xenopus laevis. Mol. Cell. . Biol 18:4262–71
     [Google Scholar]
  146. 146.  Qvist P, Huertas P, Jimeno S, Nyegaard M, Hassan MJ et al. 2011. CtIP mutations cause Seckel and Jawad syndromes. PLOS Genet 7:e1002310
     [Google Scholar]
  147. 147.  Rai R, Dai H, Multani AS, Li K, Chin K et al. 2006. BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer Cell 10:145–57
     [Google Scholar]
  148. 148.  Rakic P 1988. Specification of cerebral cortical areas. Science 241:170–76
     [Google Scholar]
  149. 149.  Ramdas Nair A, Singh P, Salvador Garcia D, Rodriguez-Crespo D, Egger B, Cabernard C 2016. The microcephaly-associated protein Wdr62/cg7337 is required to maintain centrosome asymmetry in Drosophila neuroblasts. Cell Rep 14:1100–13
     [Google Scholar]
  150. 150.  Reillo I, de Juan Romero C, Garcia-Cabezas MA, Borrell V 2011. A role for intermediate radial glia in the tangential expansion of the mammalian cerebral cortex. Cereb. Cortex 21:1674–94
     [Google Scholar]
  151. 151.  Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R et al. 2017. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nat. Genet. 49:537–49
     [Google Scholar]
  152. 152.  Rhyu MS, Jan LY, Jan YN 1994. Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells. Cell 76:477–91
     [Google Scholar]
  153. 153.  Ruan Q, Wang Q, Xie S, Fang Y, Darzynkiewicz Z et al. 2004. Polo-like kinase 3 is Golgi localized and involved in regulating Golgi fragmentation during the cell cycle. Exp. Cell Res. 294:51–59
     [Google Scholar]
  154. 154.  Schmidt TI, Kleylein-Sohn J, Westendorf J, Le Clech M Lavoie SB et al. 2009. Control of centriole length by CPAP and CP110. Curr. Biol. 19:1005–11
     [Google Scholar]
  155. 155.  Shaheen R, Faqeih E, Ansari S, Abdel-Salam G, Al-Hassnan ZN et al. 2014. Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Res 24:291–99
     [Google Scholar]
  156. 156.  Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A et al. 2004. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat. Genet. 36:69–76
     [Google Scholar]
  157. 157.  Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ et al. 2010. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat. Genet. 42:245–49
     [Google Scholar]
  158. 158.  Sidman RL, Miale IL, Feder N 1959. Cell proliferation and migration in the primitive ependymal zone: an autoradiographic study of histogenesis in the nervous system. Exp. Neurol. 1:322–33
     [Google Scholar]
  159. 159.  Siller KH, Doe CQ 2009. Spindle orientation during asymmetric cell division. Nat. Cell Biol. 11:365–74
     [Google Scholar]
  160. 160.  Sir JH, Barr AR, Nicholas AK, Carvalho OP, Khurshid M et al. 2011. A primary microcephaly protein complex forms a ring around parental centrioles. Nat. Genet. 43:1147–53
     [Google Scholar]
  161. 161.  Smart IH, Dehay C, Giroud P, Berland M, Kennedy H 2002. Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb. Cortex 12:37–53
     [Google Scholar]
  162. 162.  Spana EP, Doe CQ 1996. Numb antagonizes Notch signaling to specify sibling neuron cell fates. Neuron 17:21–26
     [Google Scholar]
  163. 163.  Spana EP, Kopczynski C, Goodman CS, Doe CQ 1995. Asymmetric localization of numb autonomously determines sibling neuron identity in the Drosophila CNS. Development 121:3489–94
     [Google Scholar]
  164. 164.  Sunkel CE, Glover DM 1988. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J. Cell Sci. 89:25–38
     [Google Scholar]
  165. 165.  Takahashi T, Nowakowski RS, Caviness VS Jr. 1996. The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis. J. Neurosci. 16:6183–96
     [Google Scholar]
  166. 166.  Tallinen T, Chung JY, Biggins JS, Mahadevan L 2014. Gyrification from constrained cortical expansion. PNAS 111:12667–72
     [Google Scholar]
  167. 167.  Tamamaki N, Fujimori KE, Takauji R 1997. Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J. Neurosci. 17:8313–23
     [Google Scholar]
  168. 168.  Tang CJ, Fu RH, Wu KS, Hsu WB, Tang TK 2009. CPAP is a cell-cycle regulated protein that controls centriole length. Nat. Cell Biol. 11:825–31
     [Google Scholar]
  169. 169.  Tang CJ, Lin SY, Hsu WB, Lin YN, Wu CT et al. 2011. The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation. EMBO J 30:4790–804
     [Google Scholar]
  170. 170.  Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H et al. 2004. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am. J. Hum. Genet. 75:261–66
     [Google Scholar]
  171. 171.  Uemura T, Shepherd S, Ackerman L, Jan LY, Jan YN 1989. numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos. Cell 58:349–60
     [Google Scholar]
  172. 172.  van der Voet M, Berends CW, Perreault A, Nguyen-Ngoc T, Gonczy P et al. 2009. NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Gα. Nat. Cell Biol. 11:269–77
     [Google Scholar]
  173. 173.  Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH et al. 1998. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93:467–76
     [Google Scholar]
  174. 174.  Vemuri MC, Schiller E, Naegele JR 2001. Elevated DNA double strand breaks and apoptosis in the CNS of scid mutant mice. Cell Death Differ 8:245–55
     [Google Scholar]
  175. 175.  Verloes A, Drunat S, Gressens P, Passemard S 1993. Primary autosomal recessive microcephalies and Seckel syndrome spectrum disorders. GeneReviews MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJH Bean et al. Seattle: Univ. Wash. Press https://www.ncbi.nlm.nih.gov/books/NBK9587
    [Google Scholar]
  176. 176.  Wakefield JG, Bonaccorsi S, Gatti M 2001. The Drosophila protein Asp is involved in microtubule organization during spindle formation and cytokinesis. J. Cell Biol. 153:637–48
     [Google Scholar]
  177. 177.  Wang X, Tsai JW, Imai JH, Lian WN, Vallee RB, Shi SH 2009. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461:947–55
     [Google Scholar]
  178. 178.  Woods CG 2004. Human microcephaly. Curr. Opin. Neurobiol. 14:112–17
     [Google Scholar]
  179. 179.  Woodworth MB, Custo Greig L, Kriegstein AR, Macklis JD 2012. SnapShot: cortical development. Cell 151:918
     [Google Scholar]
  180. 180.  Xu D, Zhang F, Wang Y, Sun Y, Xu Z 2014. Microcephaly-associated protein WDR62 regulates neurogenesis through JNK1 in the developing neocortex. Cell Rep 6:104–16
     [Google Scholar]
  181. 181.  Xu X, Lee J, Stern DF 2004. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. J. Biol. Chem. 279:34091–94
     [Google Scholar]
  182. 182.  Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E et al. 2014. A Drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell 159:200–14
     [Google Scholar]
  183. 183.  Yamashita YM, Mahowald AP, Perlin JR, Fuller MT 2007. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315:518–21
     [Google Scholar]
  184. 184.  Yang YJ, Baltus AE, Mathew RS, Murphy EA, Evrony GD et al. 2012. Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation. Cell 151:1097–112
     [Google Scholar]
  185. 185.  Yigit G, Brown KE, Kayserili H, Pohl E, Caliebe A et al. 2015. Mutations in CDK5RAP2 cause Seckel syndrome. Mol. Genet. Genom. Med. 3:467–80
     [Google Scholar]
  186. 186.  Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L et al. 2010. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat. Genet. 42:1015–20
     [Google Scholar]
  187. 187.  Zhang X, Chen MH, Wu X, Kodani A, Fan J et al. 2016. Cell-type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell 166:1147–62
     [Google Scholar]
  188. 188.  Zhang X, Ling J, Barcia G, Jing L, Wu J et al. 2014. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am. J. Hum. Genet. 94:547–58
     [Google Scholar]
  189. 189.  Zhong W, Feder JN, Jiang MM, Jan LY, Jan YN 1996. Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron 17:43–53
     [Google Scholar]
/content/journals/10.1146/annurev-genom-083117-021441
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The Genetics of Primary Microcephaly
Annual Review of Genomics and Human Genetics 19, 177 (2018); https://doi.org/10.1146/annurev-genom-083117-021441
/content/journals/10.1146/annurev-genom-083117-021441
/content/journals/10.1146/annurev-genom-083117-021441
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