A Localized Wnt Signal Orients Asymmetric Stem Cell Division in Vitro

Stem cells orient cell division and generate a distinct cell fate based on position relative to the Wnt source. Developmental signals such as Wnts are often presented to cells in an oriented manner. To examine the consequences of local Wnt signaling, we immobilized Wnt proteins on beads and introduced them to embryonic stem cells in culture. At the single-cell level, the Wnt-bead induced asymmetric distribution of Wnt–β-catenin signaling components, oriented the plane of mitotic division, and directed asymmetric inheritance of centrosomes. Before cytokinesis was completed, the Wnt-proximal daughter cell expressed high levels of nuclear β-catenin and pluripotency genes, whereas the distal daughter cell acquired hallmarks of differentiation. We suggest that a spatially restricted Wnt signal induces an oriented cell division that generates distinct cell fates at predictable positions relative to the Wnt source.

[1]  Julia Tischler,et al.  Stem cells: A sporadic super state , 2012, Nature.

[2]  Michel Bornens,et al.  The Centrosome in Cells and Organisms , 2012, Science.

[3]  K. Hochedlinger,et al.  Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. , 2011, Cell stem cell.

[4]  B. Goldstein,et al.  How signaling between cells can orient a mitotic spindle. , 2011, Seminars in cell & developmental biology.

[5]  Hitoshi Sawa,et al.  Wnt Regulates Spindle Asymmetry to Generate Asymmetric Nuclear β-Catenin in C. elegans , 2011, Cell.

[6]  T. Blauwkamp,et al.  Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells , 2011, Nature Cell Biology.

[7]  M. Davidson,et al.  Rapid three-dimensional isotropic imaging of living cells using Bessel beam plane illumination , 2011, Nature Methods.

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

[9]  Bulent Ataman,et al.  Trans-Synaptic Transmission of Vesicular Wnt Signals through Evi/Wntless , 2009, Cell.

[10]  S. Shi,et al.  Asymmetric centrosome inheritance maintains neural progenitors in neocortex , 2009, Nature.

[11]  J. Nichols,et al.  Klf4 reverts developmentally programmed restriction of ground state pluripotency , 2009, Development.

[12]  K. Lao,et al.  Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. , 2008, Cell stem cell.

[13]  B. Doble,et al.  The ground state of embryonic stem cell self-renewal , 2008, Nature.

[14]  H. Niwa,et al.  Identification and characterization of subpopulations in undifferentiated ES cell culture , 2008, Development.

[15]  M. Fuller,et al.  Asymmetric centrosome behavior and the mechanisms of stem cell division , 2008, The Journal of cell biology.

[16]  J. Nichols,et al.  Nanog safeguards pluripotency and mediates germline development , 2007, Nature.

[17]  N. Terada,et al.  A Heterogeneous Expression Pattern for Nanog in Embryonic Stem Cells , 2007, Stem cells.

[18]  R. McKay,et al.  New cell lines from mouse epiblast share defining features with human embryonic stem cells , 2007, Nature.

[19]  R. Nusse,et al.  Purified Wnt5a Protein Activates or Inhibits β-Catenin–TCF Signaling Depending on Receptor Context , 2006, PLoS biology.

[20]  Cori Bargmann,et al.  Wnt signals and frizzled activity orient anterior-posterior axon outgrowth in C. elegans. , 2006, Developmental cell.

[21]  B. Goldstein,et al.  Wnt signals can function as positional cues in establishing cell polarity. , 2006, Developmental cell.

[22]  M. Surani,et al.  Generation of stella‐GFP transgenic mice: A novel tool to study germ cell development , 2006, Genesis.

[23]  Takeshi Oshima,et al.  Mitogenic Influence of Human R-Spondin1 on the Intestinal Epithelium , 2005, Science.

[24]  W. Wood,et al.  Multiple Wnt signaling pathways converge to orient the mitotic spindle in early C. elegans embryos. , 2004, Developmental cell.

[25]  M. Fuller,et al.  Orientation of Asymmetric Stem Cell Division by the APC Tumor Suppressor and Centrosome , 2003, Science.

[26]  I. Weissman,et al.  Wnt proteins are lipid-modified and can act as stem cell growth factors , 2003, Nature.

[27]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in X Inactivation , 2003, Science.

[28]  M. Bornens,et al.  Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein. , 2000, Journal of cell science.

[29]  P. Casey,et al.  beta-Catenin is a Nek2 substrate involved in centrosome separation. , 2008, Genes & development.

[30]  P. Greengard,et al.  Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor , 2004, Nature Medicine.