Proliferation control in neural stem and progenitor cells

Nature Reviews Neuroscience

Volumn 16, Issue 11, 2015, Pages 647-659

  Homem, Catarina C F ^a,b   Repic, Marko ^a   Knoblich, Jürgen A ^a  

^a INSTITUTE OF MOLECULAR BIOTECHNOLOGY   (Austria)

^b NOVA MEDICAL SCHOOL   (Portugal)

Author keywords

[No Author keywords available]

Indexed keywords

AGE; ALEXANDER DISEASE; ASYMMETRIC CELL DIVISION; BRAIN DEVELOPMENT; CELL CYCLE REGULATION; CELL LINEAGE; CELL PROLIFERATION; DEVELOPMENTAL STAGE; DROSOPHILA MELANOGASTER; ENDOCRINE FUNCTION; HUMAN; MAMMAL; METABOLISM; MICROCEPHALY; NERVE CELL DIFFERENTIATION; NERVOUS SYSTEM DEVELOPMENT; NEURAL STEM CELL; NONHUMAN; NUTRITION; PRIORITY JOURNAL; REVIEW; STEM CELL; STEM CELL RESEARCH; ANIMAL; CYTOLOGY; GLIA; GROWTH, DEVELOPMENT AND AGING; MOUSE; NEOCORTEX; PATHOLOGY; PHYSIOLOGY;

ANIMALS; CELL PROLIFERATION; DROSOPHILA MELANOGASTER; HUMANS; MICE; MICROCEPHALY; NEOCORTEX; NEURAL STEM CELLS; NEUROGLIA; STEM CELLS;

EID: 84945469911     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn4021     Document Type: Review

References (171)

1. Neufeld, T. P., de la Cruz, A. F., Johnston, L. A. & Edgar, B. A. Coordination of growth and cell division in the Drosophila wing. Cell 93, 1183-1193 (1998).
2. Lanet, E., Gould, A. P. & Maurange, C. Protection of neuronal diversity at the expense of neuronal numbers during nutrient restriction in the Drosophila visual system. Cell Rep. 3, 587-594 (2013).
3. Janssens, D. H. et al. Earmuff restricts progenitor cell potential by attenuating the competence to respond to self-renewal factors. Development 141, 1036-1046 (2014).
4. Gao, P. et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex. Cell 159, 775-788 (2014).
5. Wang, Y. C. et al. Drosophila intermediate neural progenitors produce lineage-dependent related series of diverse neurons. Development 141, 253-258 (2014).
6. Ming, G. L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687-702 (2011).
7. Homem, C. C. & Knoblich, J. A. Drosophila neuroblasts: a model for stem cell biology. Development 139, 4297-4310 (2012).
8. Chang, K. C., Wang, C. & Wang, H. Balancing self-renewal and differentiation by asymmetric division: Insights from brain tumor suppressors in Drosophila neural stem cells. Bioessays 34, 301-310 (2012).
9. Xie, Y. et al. The Drosophila Sp8 transcription factor Buttonhead prevents premature differentiation of intermediate neural progenitors. eLife 3, e03596 (2014).
10. Zhu, S., Barshow, S., Wildonger, J., Jan, L. Y. & Jan, Y. N. Ets transcription factor Pointed promotes the generation of intermediate neural progenitors in Drosophila larval brains. Proc. Natl Acad. Sci. USA 108, 20615-20620 (2011).
11. Komori, H., Xiao, Q., Janssens, D. H., Dou, Y. & Lee, C. Y. Trithorax maintains the functional heterogeneity of neural stem cells through the transcription factor Buttonhead. eLife 3, e03502 (2014).
12. Xiao, Q., Komori, H. & Lee, C. Y. klumpfuss distinguishes stem cells from progenitor cells during asymmetric neuroblast division. Development 139, 2670-2680 (2012).
13. Bowman, S. K. et al. The tumor suppressors Brat and Numb regulate transit-Amplifying neuroblast lineages in Drosophila. Dev. Cell 14, 535-546 (2008).
14. Wang, H. et al. Aurora A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes Dev. 20, 3453-3463 (2006).
15. Almeida, M. S. & Bray, S. J. Regulation of post-embryonic neuroblasts by Drosophila Grainyhead. Mech. Dev. 122, 1282-1293 (2005).
16. Berger, C. et al. FACS purification and transcriptome analysis of Drosophila neural stem cells reveals a role for Klumpfuss in self-renewal. Cell Rep. 2, 407-418 (2012).
17. Zacharioudaki, E. & Magadi, S. S. & Delidakis, C. bHLH O proteins are crucial for Drosophila neuroblast self-renewal and mediate Notch-induced overproliferation. Development 139, 1258-1269 (2012).
18. San-Juán, B. P. & Baonza, A. The bHLH factor deadpan is a direct target of Notch signaling and regulates neuroblast self-renewal in Drosophila. Dev. Biol. 352, 70-82 (2011).
19. Song, Y. & Lu, B. Regulation of cell growth by Notch signaling and its differential requirement in normal versus tumor-forming stem cells in Drosophila. Genes Dev. 25, 2644-2658 (2011).
20. Schweisguth, F. Notch signaling activity. Curr. Biol. 14, R129-R138 (2004).
21. Couturier, L., Vodovar, N. & Schweisguth, F. Endocytosis by Numb breaks Notch symmetry at cytokinesis. Nat. Cell Biol. 14, 131-139 (2012).
22. Harris, R. E., Pargett, M., Sutcliffe, C., Umulis, D. & Ashe, H. L. Brat promotes stem cell differentiation via control of a bistable switch that restricts BMP signaling. Dev. Cell 20, 72-83 (2011).
23. Marchetti, G., Reichardt, I., Knoblich, J. A. & Besse, F. The TRIM-NHL protein Brat promotes axon maintenance by repressing src64B expression. J. Neurosci. 34, 13855-13864 (2014).
24. Weng, M., Golden, K. L. & Lee, C. Y. dFezf/Earmuff maintains the restricted developmental potential of intermediate neural progenitors in Drosophila. Dev. Cell 18, 126-135 (2010).
25. Koe, C. T. et al. The Brm-HDAC3-Erm repressor complex suppresses dedifferentiation in Drosophila type II neuroblast lineages. eLife 3, e01906 (2014).
26. Eroglu, E. et al. SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells. Cell 156, 1259-1273 (2014).
27. Mori, T., Buffo, A. & Gotz, M. The novel roles of glial cells revisited: the contribution of radial glia and astrocytes to neurogenesis. Curr. Top. Dev. Biol. 69, 67-99 (2005).
28. Gotz, M. & Huttner, W. B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell. Biol. 6, 777-788 (2005).
29. Noctor, S. C., Martínez-Cerdeño, V., Ivic, L. & Kriegstein, A. R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7, 136-144 (2004).
30. Pontious, A., Kowalczyk, T., Englund, C. & Hevner, R. F. Role of intermediate progenitor cells in cerebral cortex development. Dev. Neurosci. 30, 24-32 (2008).
31. Gal, J. S. et al. Molecular and morphological heterogeneity of neural precursors in the mouse neocortical proliferative zones. J. Neurosci. 26, 1045-1056 (2006).
32. Stancik, E. K., Navarro-Quiroga, I., Sellke, R. & Haydar, T. F. Heterogeneity in ventricular zone neural precursors contributes to neuronal fate diversity in the postnatal neocortex. J. Neurosci. 30, 7028-7036 (2010).
33. Hansen, D. V., Lui, J. H., Parker, P. R. & Kriegstein, A. R. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464, 554-561 (2010).
34. Reillo, I., de Juan Romero, C., García-Cabezas, M. A. & Borrell, V. A role for intermediate radial glia in the tangential expansion of the mammalian cerebral cortex. Cereb. Cortex 21, 1674-1694 (2011).
35. Kelava, I. et al. 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, 469-481 (2012).
36. Betizeau, M. et al. Precursor diversity and complexity of lineage relationships in the outer subventricular zone of the primate. Neuron 80, 442-457 (2013).
37. Chenn, A. & McConnell, S. K. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82, 631-641 (1995).
38. Zhong, W., Feder, J. N., Jiang, M. M., Jan, L. Y. & Jan, Y. N. Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron 17, 43-53 (1996).
39. Kosodo, Y. et al. Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J. 23, 2314-2324 (2004).
40. Izumi, Y., Ohta, N., Hisata, K., Raabe, T. & Matsuzaki, F. Drosophila Pins-binding protein Mud regulates spindle-polarity coupling and centrosome organization. Nat. Cell Biol. 8, 586-593 (2006).
41. Postiglione, M. P. et al. Mouse inscuteable induces apical-basal spindle orientation to facilitate intermediate progenitor generation in the developing neocortex. Neuron 72, 269-284 (2011).
42. Morin, X., Jaouen, F. & Durbec, P. Control of planar divisions by the G protein regulator LGN maintains progenitors in the chick neuroepithelium. Nat. Neurosci. 10, 1440-1448 (2007).
43. Konno, D. et al. Neuroepithelial progenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis. Nat. Cell Biol. 10, 93-101 (2008).
44. Yu, F. et al. A mouse homologue of Drosophila pins can asymmetrically localize and substitute for pins function in Drosophila neuroblasts. J. Cell Sci. 116, 887-896 (2003).
45. Mora-Bermudez, F., Matsuzaki, F. & Huttner, W. B. Specific polar subpopulations of astral microtubules control spindle orientation and symmetric neural stem cell division. eLife 3, e02875 (2014).
46. Shitamukai, A., Konno, D. & Matsuzaki, F. Oblique radial glial divisions in the developing mouse neocortex induce self-renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors. J. Neurosci. 31, 3683-3695 (2011).
47. Bultje, R. S. et al. Mammalian Par3 regulates progenitor cell asymmetric division via notch signaling in the developing neocortex. Neuron 63, 189-202 (2009).
48. Conduit, P. T. & Raff, J. W. Cnn dynamics drive centrosome size asymmetry to ensure daughter centriole retention in Drosophila neuroblasts. Curr. Biol. 20, 2187-2192 (2010).
49. Januschke, J., Llamazares, S., Reina, J. & Gonzalez, C. Drosophila neuroblasts retain the daughter centrosome. Nat. Commun. 2, 243 (2011).
50. Wang, X. et al. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461, 947-955 (2009).
51. Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331-344 (2010).
52. Paridaen, J. T., Wilsch-Brauninger, M. & Huttner, W. B. Asymmetric inheritance of centrosome-Associated primary cilium membrane directs ciliogenesis after cell division. Cell 155, 333-344 (2013).
53. Insolera, R., Bazzi, H., Shao, W., Anderson, K. V. & Shi, S. H. Cortical neurogenesis in the absence of centrioles. Nat. Neurosci. 17, 1528-1535 (2014).
54. Pierfelice, T., Alberi, L. & Gaiano, N. Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69, 840-855 (2011).
55. Kawaguchi, D., Yoshimatsu, T., Hozumi, K. & Gotoh, Y. Selection of differentiating cells by different levels of delta-like 1 among neural precursor cells in the developing mouse telencephalon. Development 135, 3849-3858 (2008).
56. Yoon, K. J. et al. Mind bomb 1 expressing intermediate progenitors generate notch signaling to maintain radial glial cells. Neuron 58, 519-531 (2008).
57. Dong, Z., Yang, N., Yeo, S. Y., Chitnis, A. & Guo, S. Intralineage directional Notch signaling regulates self-renewal and differentiation of asymmetrically dividing radial glia. Neuron 74, 65-78 (2012).
58. Nelson, B. R., Hodge, R. D., Bedogni, F. & Hevner, R. F. Dynamic interactions between intermediate neurogenic progenitors and radial glia in embryonic mouse neocortex: potential role in Dll1 Notch signaling. J. Neurosci. 33, 9122-9139 (2013).
59. Ohtsuka, T., Sakamoto, M., Guillemot, F. & Kageyama, R. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J. Biol. Chem. 276, 30467-30474 (2001).
60. Mizutani, K., Yoon, K., Dang, L., Tokunaga, A. & Gaiano, N. Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature 449, 351-355 (2007).
61. Shimojo, H., Ohtsuka, T. & Kageyama, R. Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58, 52-64 (2008).
62. Baek, J. H., Hatakeyama, J., Sakamoto, S., Ohtsuka, T. & Kageyama, R. Persistent and high levels of Hes1 expression regulate boundary formation in the developing central nervous system. Development 133, 2467-2476 (2006).
63. Calegari, F., Haubensak, W., Haffner, C. & Huttner, W. B. Selective lengthening of the cell cycle in the neurogenic subpopulation of neural progenitor cells during mouse brain development. J. Neurosci. 25, 6533-6538 (2005).
64. Arai, Y. et al. Neural stem and progenitor cells shorten S phase on commitment to neuron production. Nat. Commun. 2, 154 (2011).
65. Calegari, F. & Huttner, W. B. An inhibition of cyclin-dependent kinases that lengthens, but does not arrest, neuroepithelial cell cycle induces premature neurogenesis. J. Cell Sci. 116, 4947-4955 (2003).
66. Pilaz, L. J. et al. Forced G1 phase reduction alters mode of division, neuron number, and laminar phenotype in the cerebral cortex. Proc. Natl Acad. Sci. USA 106, 21924-21929 (2009).
67. Lange, C., Huttner, W. B. & Calegari, F. Cdk4/cyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors. Cell Stem Cell 5, 320-331 (2009).
68. Takahashi, T., Nowakowski, R. S. & Caviness, V. S. J. The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J. Neurosci. 15, 6046-6057 (1995).
69. Kohwi, M. & Doe, C. Q. Temporal fate specification and neural progenitor competence during development. Nat. Rev. Neurosci. 14, 823-838 (2013).
70. Britton, J. S. & Edgar, B. A. Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development 125, 2149-2158 (1998).
71. Speder, P. & Brand, A. H. Gap junction proteins in the blood-brain barrier control nutrient-dependent reactivation of Drosophila neural stem cells. Dev. Cell. 30, 309-321 (2014).
72. Sousa-Nunes, R., Yee, L. L. & Gould, A. P. Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature 471, 508-512 (2011).
73. Chell, J. M. & Brand, A. H. Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell 143, 1161-1173 (2010).
74. Egger, B., Gold, K. S. & Brand, A. H. Regulating the balance between symmetric and asymmetric stem cell division in the developing brain. Fly 5, 237-241 (2011).
75. Liu, J., Speder, P. & Brand, A. H. Control of brain development and homeostasis by local and systemic insulin signalling. Diabetes Obes. Metab. 16, S16-S20 (2014).
76. Lehtinen, M. K. et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69, 893-905 (2011).
77. Popken, G. J. et al. In vivo effects of insulin-like growth factor I (IGF I) on prenatal and early postnatal development of the central nervous system. Eur. J. Neurosci. 19, 2056-2068 (2004).
78. Brody, T. & Odenwald, W. F. Programmed transformations in neuroblast gene expression during Drosophila CNS lineage development. Dev. Biol. 226, 34-44 (2000).
79. Isshiki, T., Pearson, B., Holbrook, S. & Doe, C. Q. Drosophila neuroblasts sequentially express transcription factors which specify the temporal identity of their neuronal progeny. Cell 106, 511-521 (2001).
80. Kambadur, R. et al. Regulation of POU genes by castor and hunchback establishes layered compartments in the Drosophila CNS. Genes Dev. 12, 246-260 (1998).
81. Pearson, B. J. & Doe, C. Q. Regulation of neuroblast competence in Drosophila. Nature 425, 624-628 (2003).
82. Grosskortenhaus, R., Robinson, K. J. & Doe, C. Q. Pdm and Castor specify late-born motor neuron identity in the NEUROBLAST7 1 lineage. Genes Dev. 20, 2618-2627 (2006).
83. Maurange, C., Cheng, L. & Gould, A. P. Temporal transcription factors and their targets schedule the end of neural proliferation in Drosophila. Cell 133, 891-902 (2008).
84. Chai, P. C., Liu, Z., Chia, W. & Cai, Y. Hedgehog signaling acts with the temporal cascade to promote neuroblast cell cycle exit. PLoS Biol. 11, e1001494 (2013).
85. Homem, C. C. et al. Ecdysone and mediator change energy metabolism to terminate proliferation in Drosophila neural stem cells. Cell 158, 874-888 (2014).
86. Siegrist, S. E., Haque, N. S., Chen, C. H., Hay, B. A. & Hariharan, I. K. Inactivation of both foxo and reaper promotes long-Term adult neurogenesis in Drosophila. Curr. Biol. 20, 643-648 (2010).
87. White, K. et al. Genetic control of programmed cell death in Drosophila. Science 264, 667-683 (1994).
88. Bello, B. C., Hirth, F. & Gould, A. P. A pulse of the Drosophila Hox protein Abdominal A schedules the end of neural proliferation via neuroblast apoptosis. Neuron 37, 209-219 (2003).
89. Arya, R., Sarkissian, T., Tan, Y. & White, K. Neural stem cell progeny regulate stem cell death in a Notch and Hox dependent manner. Cell Death Differ. 22, 1378-1387 (2015).
90. Cenci, C. & Gould, A. P. Drosophila Grainyhead specifies late programmes of neural proliferation by regulating the mitotic activity and Hox-dependent apoptosis of neuroblasts. Development 132, 3835-3845 (2005).
91. Bayraktar, O. A. & Doe, C. Q. Combinatorial temporal patterning in progenitors expands neural diversity. Nature 498, 449-455 (2013).
92. Fog, C. K., Galli, G. G. & Lund, A. H. PRDM proteins: important players in differentiation and disease. Bioessays 34, 50-60 (2012).
93. Pinheiro, I. et al. Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell 150, 948-960 (2012).
94. Suzuki, T., Kaido, M., Takayama, R. & Sato, M. A temporal mechanism that produces neuronal diversity in the Drosophila visual center. Dev. Biol. 380, 12-24 (2013).
95. Li, X. et al. Temporal patterning of Drosophila medulla neuroblasts controls neural fates. Nature 498, 456-462 (2013).
96. Frantz, G. D. & McConnell, S. K. Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron 17, 55-61 (1996).
97. Desai, A. R. & McConnell, S. K. Progressive restriction in fate potential by neural progenitors during cerebral cortical development. Development 127, 2863-2872 (2000).
98. Gaspard, N. et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455, 351-357 (2008).
99. Shen, Q. et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nat. Neurosci. 9, 743-751 (2006).
100. Eiraku, M. et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3, 519-532 (2008).
101. Franco, S. J. et al. Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 337, 746-749 (2012).
102. Guo, C. et al. Fezf2 expression identifies a multipotent progenitor for neocortical projection neurons, astrocytes, and oligodendrocytes. Neuron 80, 1167-1174 (2013).
103. Götz, M., Stoykova, A. & Gruss, P. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21, 1031-1044 (1998).
104. Quaggin, S. E., Heuvel, G. B., Golden, K., Bodmer, R. & Igarashi, P. Primary structure, neural-specific expression, and chromosomal localization of Cux 2, a second murine homeobox gene related to Drosophila cut. J. Biol. Chem. 271, 22624-22634 (1996).
105. Naka, H., Nakamura, S., Shimazaki, T. & Okano, H. Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development. Nat. Neurosci. 11, 1014-1023 (2008).
106. Alsio, J. M., Tarchini, B., Cayouette, M. & Livesey, F. J. Ikaros promotes early-born neuronal fates in the cerebral cortex. Proc. Natl Acad. Sci. USA 110, E716-E725 (2013).
107. Mattar, P., Ericson, J., Blackshaw, S. & Cayouette, M. A conserved regulatory logic controls temporal identity in mouse neural progenitors. Neuron 85, 497-504 (2015).
108. Culican, S. M., Baumrind, N. L., Yamamoto, M. & Pearlman, A. L. Cortical radial glia: identification in tissue culture and evidence for their transformation to astrocytes. J. Neurosci. 10, 684-692 (1990).
109. Rowitch, D. H. & Kriegstein, A. R. Developmental genetics of vertebrate glial-cell specification. Nature 468, 214-222 (2010).
110. Fan, G. et al. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132, 3345-3356 (2005).
111. Chambers, C. B. et al. Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors. Development 128, 689-702 (2001).
112. Namihira, M. et al. Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev. Cell 16, 245-255 (2009).
113. Hirabayashi, Y. et al. Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition. Neuron 63, 600-613 (2009).
114. Barnabe-Heider, F. et al. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin 1. Neuron 48, 253-265 (2005).
115. Homem, C. C., Reichardt, I., Berger, C., Lendl, T. & Knoblich, J. A. Long-Term live cell imaging and automated 4D analysis of neuroblast lineages. PLoS ONE 8, e79588 (2013).
116. Truman, J. W. & Bate, M. Spatial and temporal patterns of neurogenesis in the central nervous system of Drosophila melanogaster. Dev. Biol. 125, 145-157 (1988).
117. Layalle, S., Arquier, N. & Leopold, P. The TOR pathway couples nutrition and developmental timing in Drosophila. Dev. Cell 15, 568-577 (2008).
118. Colombani, J., Andersen, D. S. & Leopold, P. Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. Science 336, 582-585 (2012).
119. Garelli, A., Gontijo, A. M., Miguela, V., Caparros, E. & Dominguez, M. Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science 336, 579-582 (2012).
120. Frerman, F. E. & Goodman, S. I. Deficiency of electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts. Proc. Natl Acad. Sci. USA 82, 4517-4520 (1985).
121. Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226-230 (2013).
122. McIntyre, R. E. et al. Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. PLoS Genet. 8, e1003022 (2012).
123. Martin, C. A. et al. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat. Genet. 46, 1283-1292 (2014).
124. Buchman, J. J. et al. Cdk5rap2 interacts with pericentrin to maintain the neural progenitor pool in the developing neocortex. Neuron 66, 386-402 (2010).
125. Barrera, J. A. et al. CDK5RAP2 regulates centriole engagement and cohesion in mice. Dev. Cell 18, 913-926 (2010).
126. Fish, J. L., Kosodo, Y., Enard, W., Paabo, S. & Huttner, W. B. Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proc. Natl Acad. Sci. USA 103, 10438-10443 (2006).
127. Rujano, M. A., Sanchez-Pulido, L., Pennetier, C., le Dez, G. & Basto, R. The microcephaly protein Asp regulates neuroepithelium morphogenesis by controlling the spatial distribution of myosin II. Nat. Cell Biol. 15, 1294-1306 (2013).
128. Buchman, J. J., Durak, O. & Tsai, L. H. ASPM regulates Wnt signaling pathway activity in the developing brain. Genes Dev. 25, 1909-1914 (2011).
129. Chen, J. F. et al. Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size. Nat. Commun. 5, 3885 (2014).
130. Gruber, R. et al. MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway. Nat. Cell Biol. 13, 1325-1334 (2011).
131. Varmark, H. et al. Asterless is a centriolar protein required for centrosome function and embryo development in Drosophila. Curr. Biol. 17, 1735-1745 (2007).
132. Dzhindzhev, N. S. et al. Asterless is a scaffold for the onset of centriole assembly. Nature 467, 714-718 (2010).
133. Giansanti, M. G., Gatti, M. & Bonaccorsi, S. The role of centrosomes and astral microtubules during asymmetric division of Drosophila neuroblasts. Development 128, 1137-1145 (2001).
134. Gilmore, E. C. & Walsh, C. A. Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdiscip. Rev. Dev. Biol. 2, 461-478 (2013).
135. Malatesta, P., Hartfuss, E. & Gotz, M. Isolation of radial glial cells by fluorescent-Activated cell sorting reveals a neuronal lineage. Development 127, 5253-5263 (2000).
136. Feng, Y. & Walsh, C. A. Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron 44, 279-293 (2004).
137. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373-379 (2013).
138. Groszer, M. et al. Negative regulation of neural stem/ progenitor cell proliferation by the PTEN tumor suppressor gene in vivo. Science 294, 2186-2189 (2001).
139. D'Gama, A. M. et al. Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann. Neurol. 77, 720-725 (2015).
140. Poduri, A. et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74, 41-48 (2012).
141. Mirzaa, G. M. & Poduri, A. Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology. Am. J. Med. Genet. C. Semin. Med. Genet. 166, 156-172 (2014).
142. Marsh, D. J. et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat. Genet. 16, 333-334 (1997).
143. Mirzaa, G. M. et al. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat. Genet. 46, 510-515 (2014).
144. Spaeth, J. M., Kim, N. H. & Boyer, T. G. Mediator and human disease. Semin. Cell. Dev. Biol. 22, 776-787 (2011).
145. Tsurusaki, Y. et al. Coffin-Siris syndrome is a SWI/ SNF complex disorder. Clin. Genet. 85, 548-554 (2014).
146. Fietz, S. A. et al. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat. Neurosci. 13, 690-699 (2010).
147. Wilkinson, R. & Wiedenheft, B. A. CRISPR method for genome engineering. F1000Prime Rep. 6, 3 (2014).
148. Kadoshima, T. et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc. Natl Acad. Sci. USA 110, 20284-20289 (2013).
149. Smart, I. H., Dehay, C., Giroud, P., Berland, M. & Kennedy, H. 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 (2002).
150. Wang, X., Tsai, J. W., LaMonica, B. & Kriegstein, A. R. A new subtype of progenitor cell in the mouse embryonic neocortex. Nat. Neurosci. 14, 555-561 (2011).
151. Lui, J. H., Hansen, D. V. & Kriegstein, A. R. Development and evolution of the human neocortex. Cell 146, 18-36 (2011).
152. Lui, J. H. et al. Radial glia require PDGFD-PDGFRβ signalling in human but not mouse neocortex. Nature 515, 264-268 (2014).
153. Hietakangas, V. & Cohen, S. M. Regulation of tissue growth through nutrient sensing. Annu. Rev. Genet. 43, 389-410 (2009).
154. Gruenwald, P. Chronic fetal distress and placental insufficiency. Biol. Neonat. 5, 215-265 (1963).
155. Cheng, L. Y. et al. Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila. Cell 146, 435-447 (2011).
156. Loren, C. E. et al. Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo. Genes Cells 6, 531-544 (2001).
157. Jackson, A. P. et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am. J. Hum. Genet. 71, 136-142 (2002).
158. Lin, S. Y. & Elledge, S. J. Multiple tumor suppressor pathways negatively regulate telomerase. Cell 113, 881-889 (2003).
159. Brunk, K. et al. Microcephalin coordinates mitosis in the syncytial Drosophila embryo. J. Cell Sci. 120, 3578-3588 (2007).
160. Rickmyre, J. L. et al. The Drosophila homolog of MCPH1, a human microcephaly gene, is required for genomic stability in the early embryo. J. Cell Sci. 120, 3565-3577 (2007).
161. Bilguvar, K. et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207-210 (2010).
162. Nicholas, A. K. et al. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat. Genet. 42, 1010-1014 (2010).
163. Yu, T. W. et al. Mutations in WDR62, encoding a centrosome-Associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat. Genet. 42, 1015-1020 (2010).
164. Bond, J. et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat. Genet. 37, 353-355 (2005).
165. Guernsey, D. L. et al. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am. J. Hum. Genet. 87, 40-51 (2010).
166. Bond, J. et al. ASPM is a major determinant of cerebral cortical size. Nat. Genet. 32, 316-320 (2002).
167. Kumar, A., Girimaji, S. C., Duvvari, M. R. & Blanton, S. H. Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am. J. Hum. Genet. 84, 286-290 (2009).
168. Stevens, N. R., Dobbelaere, J., Brunk, K., Franz, A. & Raff, J. W. Drosophila Ana2 is a conserved centriole duplication factor. J. Cell Biol. 188, 313-323 (2010).
169. Hussain, M. S. et al. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am. J. Hum. Genet. 90, 871-878 (2012).
170. Lin, Y. C. et al. Human microcephaly protein CEP135 binds to hSAS 6 and CPAP, and is required for centriole assembly. EMBO J. 32, 1141-1154 (2013).
171. Sir, J. H. et al. A primary microcephaly protein complex forms a ring around parental centrioles. Nat. Genet. 43, 1147-1153 (2011).