Asymmetric cell division: recent developments and their implications for tumour biology

The ability of cells to divide asymmetrically is essential for generating diverse cell types during development. The past 10 years have seen tremendous progress in our understanding of this important biological process. We have learned that localized phosphorylation events are responsible for the asymmetric segregation of cell fate determinants in mitosis and that centrosomes and microtubules play important parts in this process. The relevance of asymmetric cell division for stem cell biology has added a new dimension to the field, and exciting connections between asymmetric cell division and tumorigenesis have begun to emerge.

[1]  E. Caussinus,et al.  Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster , 2005, Nature Genetics.

[2]  R. Wharton,et al.  Drosophila Brain Tumor is a translational repressor. , 2001, Genes & development.

[3]  E. Gateff.  Malignant neoplasms of genetic origin in Drosophila melanogaster. , 1978, Science.

[4]  K. Kemphues,et al.  Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos , 1995, Cell.

[5]  Michael F Clarke,et al.  The biology of cancer stem cells. , 2007, Annual review of cell and developmental biology.

[6]  S. Shi,et al.  Asymmetric centrosome inheritance maintains neural progenitors in the , 2009 .

[7]  C. Mello,et al.  The PIE-1 protein and germline specification in C. elegans embryos , 1996, Nature.

[8]  C. M. Child.  The Organization and Cell-lineage of the Ascidian Egg , 1906 .

[9]  Takahiro Ito,et al.  Regulation of myeloid leukemia by the cell fate determinant Musashi , 2010, Nature.

[10]  G. Seydoux,et al.  Symmetry breaking and polarization of the C. elegans zygote by the polarity protein PAR-2 , 2010, Development.

[11]  Hanlee P. Ji,et al.  Next-generation DNA sequencing , 2008, Nature Biotechnology.

[12]  Hans Clevers,et al.  Crypt stem cells as the cells-of-origin of intestinal cancer , 2009, Nature.

[13]  S. Ohno.  Intercellular junctions and cellular polarity: the PAR-aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. , 2001, Current opinion in cell biology.

[14]  Y. Hotta,et al.  Proliferation pattern of postembryonic neuroblasts in the brain of Drosophila melanogaster. , 1992, Developmental biology.

[15]  Nicholas H. Brown,et al.  Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system , 1999, Nature Cell Biology.

[16]  J. Knoblich,et al.  Heterotrimeric G Proteins Direct Two Modes of Asymmetric Cell Division in the Drosophila Nervous System , 2001, Cell.

[17]  Lesilee S. Rose,et al.  Asymmetric cell division and axis formation in the embryo. , 2005, WormBook : the online review of C. elegans biology.

[18]  J. Dick,et al.  Breast cancer stem cells revealed , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Carmena.  Signaling networks during development: the case of asymmetric cell division in the Drosophila nervous system. , 2008, Developmental biology.

[20]  J. Knoblich,et al.  Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. , 2009, Genes & development.

[21]  J. Priess,et al.  Cortical flows powered by asymmetrical contraction transport PAR proteins to establish and maintain anterior-posterior polarity in the early C. elegans embryo. , 2004, Developmental cell.

[22]  S. Bowman,et al.  The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division. , 2006, Developmental cell.

[23]  Lily Yeh Jan,et al.  Development: Asymmetric cell division in the Drosophila nrevous system , 2001, Nature Reviews Neuroscience.

[24]  C. Doe,et al.  Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia , 2003, The Journal of cell biology.

[25]  C. Doe,et al.  Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. , 2006, Genes & development.

[26]  A. Hyman,et al.  Centrosomes direct cell polarity independently of microtubule assembly in C. elegans embryos , 2004, Nature.

[27]  M. Caligiuri,et al.  A cell initiating human acute myeloid leukaemia after transplantation into SCID mice , 1994, Nature.

[28]  S. van den Heuvel,et al.  A complex of LIN-5 and GPR proteins regulates G protein signaling and spindle function in C elegans. , 2003, Genes & development.

[29]  R. Mason,et al.  Pten haploinsufficiency accelerates formation of high-grade astrocytomas. , 2008, Cancer research.

[30]  G. Dontu,et al.  In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. , 2003, Genes & development.

[31]  S. Mango,et al.  CYK-4/GAP Provides a Localized Cue to Initiate Anteroposterior Polarity upon Fertilization , 2006, Science.

[32]  P. Gönczy,et al.  Coupling of cortical dynein and Gα proteins mediates spindle positioning in Caenorhabditis elegans , 2007, Nature Cell Biology.

[33]  Patrick Maisonneuve,et al.  Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis , 2004, The Journal of cell biology.

[34]  C. Doe,et al.  Miranda directs Prospero to a daughter cell during Drosophila asymmetric divisions , 1997, Nature.

[35]  Claudia S. Barros,et al.  Drosophila nonmuscle myosin II promotes the asymmetric segregation of cell fate determinants by cortical exclusion rather than active transport. , 2003, Developmental cell.

[36]  Natalie A. Kuhlman,et al.  Linking , 1986, The Fairchild Books Dictionary of Fashion.

[37]  C. Doe,et al.  The NuMA-related Mud protein binds Pins and regulates spindle orientation in Drosophila neuroblasts , 2006, Nature Cell Biology.

[38]  C. Doe,et al.  The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts , 2000, Nature.

[39]  Y. Jan,et al.  Partner of Numb Colocalizes with Numb during Mitosis and Directs Numb Asymmetric Localization in Drosophila Neural and Muscle Progenitors , 1998, Cell.

[40]  C. Mello,et al.  MEX-3 Is a KH Domain Protein That Regulates Blastomere Identity in Early C. elegans Embryos , 1996, Cell.

[41]  P. Pelicci,et al.  Numb Is an Endocytic Protein , 2000, The Journal of cell biology.

[42]  Y. Jan,et al.  Miranda Is Required for the Asymmetric Localization of Prospero during Mitosis in Drosophila , 1997, Cell.

[43]  K. Kemphues,et al.  PAR-2 is asymmetrically distributed and promotes association of P granules and PAR-1 with the cortex in C. elegans embryos. , 1996, Development.

[44]  D. Yamamoto,et al.  The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. , 1997, Development.

[45]  Y. Jan,et al.  Asymmetric segregation of Numb and Prospero during cell division , 1995, Nature.

[46]  B. Neumann,et al.  The Drosophila lethal(2)giant larvae tumor suppressor protein forms homo-oligomers and is associated with nonmuscle myosin II heavy chain , 1994, The Journal of cell biology.

[47]  Y. Jan,et al.  Miranda as a multidomain adapter linking apically localized Inscuteable and basally localized Staufen and Prospero during asymmetric cell division in Drosophila. , 1998, Genes & development.

[48]  A. Spradling,et al.  The Mother of All Stem Cells? , 2007, Science.

[49]  A. Brand,et al.  Asymmetric stem cell division: lessons from Drosophila. , 2008, Seminars in cell & developmental biology.

[50]  Elaine Fuchs,et al.  Asymmetric cell divisions promote stratification and differentiation of mammalian skin , 2005, Nature.

[51]  P. Thibault,et al.  aPKC‐mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb , 2007, The EMBO journal.

[52]  K. Mechtler,et al.  The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl , 2003, Nature.

[53]  W. Huttner,et al.  Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells , 2004, The EMBO journal.

[54]  Y. Jan,et al.  Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells , 1994, Cell.

[55]  Harold Weintraub,et al.  The pie-1 and mex-1 genes and maternal control of blastomere identity in early C. elegans embryos , 1992, Cell.

[56]  Juergen A. Knoblich,et al.  Quantitative Analysis of Protein Dynamics during Asymmetric Cell Division , 2005, Current Biology.

[57]  Yuh Nung Jan,et al.  Asymmetric cell division , 1998, Nature.

[58]  K. Prehoda,et al.  aPKC Phosphorylates Miranda to Polarize Fate Determinants during Neuroblast Asymmetric Cell Division , 2009, Current Biology.

[59]  H. Reichert,et al.  Amplification of neural stem cell proliferation by intermediate progenitor cells in Drosophila brain development , 2008, Neural Development.

[60]  M. R. Costa,et al.  Par-complex proteins promote proliferative progenitor divisions in the developing mouse cerebral cortex , 2007, Development.

[61]  E. Knust,et al.  Drosophila Atypical Protein Kinase C Associates with Bazooka and Controls Polarity of Epithelia and Neuroblasts , 2000, The Journal of cell biology.

[62]  E. Gateff,et al.  Tumor suppressor and overgrowth suppressor genes of Drosophila melanogaster: developmental aspects. , 1994, The International journal of developmental biology.

[63]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[64]  N. Fuse,et al.  Progenitor properties of symmetrically dividing Drosophila neuroblasts during embryonic and larval development. , 2010, Developmental biology.

[65]  M. Götz,et al.  The cell biology of neurogenesis , 2006, International Journal of Developmental Neuroscience.

[66]  J. Knoblich,et al.  Mechanisms of Asymmetric Stem Cell Division , 2008, Cell.

[67]  W. Chia,et al.  Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon , 2007, Nature.

[68]  J. Knoblich,et al.  DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila , 2000, Nature Cell Biology.

[69]  M. Gonzalez-Gaitan,et al.  The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila. , 2002, Developmental cell.

[70]  F. Matsuzaki,et al.  Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast , 2000, Nature.

[71]  C. Goodman,et al.  Asymmetric localization of numb autonomously determines sibling neuron identity in the Drosophila CNS. , 1995, Development.

[72]  Shigeru Kondo.  The reaction‐diffusion system: a mechanism for autonomous pattern formation in the animal skin , 2002, Genes to cells : devoted to molecular & cellular mechanisms.

[73]  A. Shevchenko,et al.  A protein complex containing Inscuteable and the Gα-binding protein Pins orients asymmetric cell divisions in Drosophila , 2000, Current Biology.

[74]  K. Mechtler,et al.  Asymmetric Segregation of the Tumor Suppressor Brat Regulates Self-Renewal in Drosophila Neural Stem Cells , 2006, Cell.

[75]  Chris Q Doe,et al.  Regulation of spindle orientation and neural stem cell fate in the Drosophila optic lobe , 2007, Neural Development.

[76]  C. Doe,et al.  Brat is a Miranda cargo protein that promotes neuronal differentiation and inhibits neuroblast self-renewal. , 2006, Developmental cell.

[77]  Kristin J. Robinson,et al.  Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation , 2006, Nature.

[78]  F. Hirth,et al.  A Pulse of the Drosophila Hox Protein Abdominal-A Schedules the End of Neural Proliferation via Neuroblast Apoptosis , 2003, Neuron.

[79]  B. Peterlin,et al.  A model of repression: CTD analogs and PIE-1 inhibit transcriptional elongation by P-TEFb. , 2003, Genes & development.

[80]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[81]  K. Kemphues,et al.  PAR-6 is a conserved PDZ domain-containing protein that colocalizes with PAR-3 in Caenorhabditis elegans embryos. , 1999, Development.

[82]  Y. Jan,et al.  Role of inscuteable in orienting asymmetric cell divisions in Drosophila , 1996, Nature.

[83]  R. Vale,et al.  Polarized Myosin Produces Unequal-Size Daughters During Asymmetric Cell Division , 2010, Science.

[84]  C. Gonzalez,et al.  The interphase microtubule aster is a determinant of asymmetric division orientation in Drosophila neuroblasts , 2010, The Journal of cell biology.

[85]  Frank Hirth,et al.  The brain tumor gene negatively regulates neural progenitor cell proliferation in the larval central brain of Drosophila , 2006, Development.

[86]  Takashi Nishimura,et al.  Linking Cell Cycle to Asymmetric Division: Aurora-A Phosphorylates the Par Complex to Regulate Numb Localization , 2008, Cell.

[87]  Y. Jan,et al.  numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos , 1989, Cell.

[88]  F. Matsuzaki,et al.  miranda localizes staufen and prospero asymmetrically in mitotic neuroblasts and epithelial cells in early Drosophila embryogenesis. , 1998, Development.

[89]  Y. Jan,et al.  Mammalian Par3 Regulates Progenitor Cell Asymmetric Division via Notch Signaling in the Developing Neocortex , 2009, Neuron.

[90]  Chris Q. Doe,et al.  Spindle orientation during asymmetric cell division , 2009, Nature Cell Biology.

[91]  Eugene Berezikov,et al.  The TRIM-NHL Protein TRIM32 Activates MicroRNAs and Prevents Self-Renewal in Mouse Neural Progenitors , 2009, Cell.

[92]  J. Campos-Ortega,et al.  inscuteable, a neural precursor gene of Drosophila, encodes a candidate for a cytoskeleton adaptor protein. , 1996, Developmental biology.

[93]  Doris Chen,et al.  Genome-wide analysis of Notch signalling in Drosophila by transgenic RNAi , 2009, Nature.

[94]  U. Heberlein,et al.  Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. , 2006, Genes & development.

[95]  D. Morton,et al.  Identification of genes required for cytoplasmic localization in early C. elegans embryos , 1988, Cell.

[96]  Tannishtha Reya,et al.  Imaging hematopoietic precursor division in real time. , 2007, Cell stem cell.

[97]  Alexey Khodjakov,et al.  Centrosome Amplification Can Initiate Tumorigenesis in Flies , 2008, Cell.

[98]  Y. Jan,et al.  Numb and Numbl are required for maintenance of cadherin-based adhesion and polarity of neural progenitors , 2007, Nature Neuroscience.

[99]  Y. Jan,et al.  Modes of protein movement that lead to the asymmetric localization of partner of Numb during Drosophila neuroblast division. , 1999, Molecular cell.

[100]  Cayetano Gonzalez,et al.  Centrosome Dysfunction in Drosophila Neural Stem Cells Causes Tumors that Are Not Due to Genome Instability , 2008, Current Biology.

[101]  E. Knust,et al.  Bazooka provides an apical cue for Inscuteable localization in Drosophila neuroblasts , 1999, Nature.

[102]  Juergen A. Knoblich.  Cell division: Asymmetric cell division during animal development , 2001, Nature Reviews Molecular Cell Biology.

[103]  Barbara Gayraud-Morel,et al.  Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells , 2006, Nature Cell Biology.

[104]  I. Raška,et al.  The Drosophila lethal(2)giant larvae tumor suppressor protein is a component of the cytoskeleton , 1994, The Journal of cell biology.

[105]  Chris Q Doe,et al.  Identification of Drosophila type II neuroblast lineages containing transit amplifying ganglion mother cells , 2008, Developmental neurobiology.

[106]  Sean X. Sun,et al.  MEX-5 enrichment in the C. elegans early embryo mediated by differential diffusion , 2010, Development.

[107]  Zang Ai-hua,et al.  Stem Cells,Cancer and Cancer Stem Cells , 2005 .

[108]  B. Dickson,et al.  A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila , 2007, Nature.

[109]  J. Ahringer,et al.  Microtubules are involved in anterior-posterior axis formation in C. elegans embryos , 2007, The Journal of cell biology.

[110]  C. Doe,et al.  Microtubule-Induced Pins/Gαi Cortical Polarity in Drosophila Neuroblasts , 2005, Cell.

[111]  Hans Clevers,et al.  Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. , 2010, Cell stem cell.

[112]  G. Seydoux,et al.  Stabilization of cell polarity by the C. elegans RING protein PAR-2. , 2006, Developmental cell.

[113]  F. Eisenhaber,et al.  Phosphorylation-Induced Autoinhibition Regulates the Cytoskeletal Protein Lethal (2) giant larvae , 2005, Current Biology.

[114]  S. Bowman,et al.  The tumor suppressors Brat and Numb regulate transit-amplifying neuroblast lineages in Drosophila. , 2008, Developmental cell.

[115]  J. Ahringer,et al.  Asymmetrically Distributed C. elegans Homologs of AGS3/PINS Control Spindle Position in the Early Embryo , 2003, Current Biology.

[116]  R. Lin,et al.  MEX-5 and MEX-6 function to establish soma/germline asymmetry in early C. elegans embryos. , 2000, Molecular cell.

[117]  Pier Paolo Di Fiore,et al.  The Tumor Suppressor p53 Regulates Polarity of Self-Renewing Divisions in Mammary Stem Cells , 2009, Cell.

[118]  C. Fraser,et al.  Translation of Polarity Cues into Asymmetric Spindle Positioning in Caenorhabditis elegans Embryos , 2022 .

[119]  Bruce A. Hay,et al.  Inactivation of Both foxo and reaper Promotes Long-Term Adult Neurogenesis in Drosophila , 2010, Current Biology.

[120]  F. Piano,et al.  Atypical protein kinase C cooperates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans. , 1998, Development.

[121]  Lessons from drosophila: The LPS receptor , 2003 .

[122]  C. Doe,et al.  The prospero transcription factor is asymmetrically localized to the cell cortex during neuroblast mitosis in Drosophila. , 1995, Development.

[123]  A. M. Turing,et al.  The chemical basis of morphogenesis , 1952, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.

[124]  Jeffrey M. Rosen,et al.  The Increasing Complexity of the Cancer Stem Cell Paradigm , 2009, Science.

[125]  K. Kemphues,et al.  par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed , 1995, Cell.

[126]  A. Suzuki,et al.  The PAR-aPKC system: lessons in polarity , 2006, Journal of Cell Science.

[127]  C. Gonzalez,et al.  Functionally unequal centrosomes drive spindle orientation in asymmetrically dividing Drosophila neural stem cells. , 2007, Developmental cell.

[128]  T. Raabe,et al.  Drosophila Pins-binding protein Mud regulates spindle-polarity coupling and centrosome organization , 2006, Nature Cell Biology.

[129]  G. Seydoux,et al.  Exclusion of germ plasm proteins from somatic lineages by cullin-dependent degradation , 2003, Nature.

[130]  G. Boulianne,et al.  Neuralized contains a phosphoinositide-binding motif required downstream of ubiquitination for delta endocytosis and notch signaling. , 2007, Developmental cell.

[131]  Anthony A Hyman,et al.  Asymmetric cell division in C. elegans: cortical polarity and spindle positioning. , 2004, Annual review of cell and developmental biology.

[132]  Sean X. Sun,et al.  Asymmetric enrichment of PIE-1 in the Caenorhabditis elegans zygote mediated by binary counterdiffusion , 2009, The Journal of cell biology.

[133]  A. Schetter,et al.  Polarization of the C. elegans zygote proceeds via distinct establishment and maintenance phases , 2003, Development.

[134]  P. Gönczy.  Mechanisms of asymmetric cell division: flies and worms pave the way , 2008, Nature Reviews Molecular Cell Biology.

[135]  A. Suzuki,et al.  Mammalian Lgl Forms a Protein Complex with PAR-6 and aPKC Independently of PAR-3 to Regulate Epithelial Cell Polarity , 2003, Current Biology.

[136]  H. Okano,et al.  Asymmetric Inheritance of Radial Glial Fibers by Cortical Neurons , 2001, Neuron.

[137]  X. Morin,et al.  Analysis of partner of inscuteable, a Novel Player of Drosophila Asymmetric Divisions, Reveals Two Distinct Steps in Inscuteable Apical Localization , 2000, Cell.

[138]  Chris Q Doe,et al.  Microtubule-induced cortical cell polarity. , 2007, Genes & development.

[139]  J. Priess,et al.  MEX-5 asymmetry in one-cell C. elegans embryos requires PAR-4- and PAR-1-dependent phosphorylation , 2008, Development.

[140]  Pier Paolo Di Fiore,et al.  NUMB controls p53 tumour suppressor activity , 2008, Nature.

[141]  C. Doe,et al.  Apical/basal spindle orientation is required for neuroblast homeostasis and neuronal differentiation in Drosophila. , 2009, Developmental cell.

[142]  C. Doe,et al.  A Mitotic Spindle-independent Cleavage Furrow Positioning Pathway Hhs Public Access , 2022 .

[143]  J. Knoblich,et al.  Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila neuroblasts , 1999, Nature.

[144]  C. Doe.  Neural stem cells: balancing self-renewal with differentiation , 2008, Development.

[145]  A. Gould,et al.  Temporal Transcription Factors and Their Targets Schedule the End of Neural Proliferation in Drosophila , 2008, Cell.

[146]  Y. Jan,et al.  The N terminus of the Drosophila Numb protein directs membrane association and actin-dependent asymmetric localization. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[147]  Y. Jan,et al.  The Drosophila myosin VI Jaguar is required for basal protein targeting and correct spindle orientation in mitotic neuroblasts. , 2003, Developmental cell.

[148]  C. Doe,et al.  Extrinsic cues, intrinsic cues and microfilaments regulate asymmetric protein localization in Drosophila neuroblasts , 1997, Current Biology.

[149]  M. Roldán,et al.  Spindle alignment is achieved without rotation after the first cell cycle in Drosophila embryonic neuroblasts , 2009, Development.