Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 311 (5767): 1609-1612

Copyright © 2006 by the American Association for the Advancement of Science

{alpha}E-Catenin Controls Cerebral Cortical Size by Regulating the Hedgehog Signaling Pathway

Wen-Hui Lien,1,2* Olga Klezovitch,1* Tania E. Fernandez,1 Jeff Delrow,3 Valeri Vasioukhin1{dagger}

Abstract: During development, cells monitor and adjust their rates of accumulation to produce organs of predetermined size. We show here that central nervous system–specific deletion of the essential adherens junction gene, {alpha}E-catenin, causes abnormal activation of the hedgehog pathway, resulting in shortening of the cell cycle, decreased apoptosis, and cortical hyperplasia. We propose that {alpha}E-catenin connects cell-density–dependent adherens junctions with the developmental hedgehog pathway and that this connection may provide a negative feedback loop controlling the size of developing cerebral cortex.

1 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
2 Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
3 Genomics Resource, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: vvasiouk{at}

{alpha}-Catenin is an inhibitor of transcription.
R. L. Daugherty, L. Serebryannyy, A. Yemelyanov, A. S. Flozak, H.-J. Yu, S. T. Kosak, P. deLanerolle, and C. J. Gottardi (2014)
PNAS 111, 5260-5265
   Abstract »    Full Text »    PDF »
Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates.
J. Hatakeyama, Y. Wakamatsu, A. Nagafuchi, R. Kageyama, R. Shigemoto, and K. Shimamura (2014)
Development 141, 1671-1682
   Abstract »    Full Text »    PDF »
The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice.
J.-C. Xu, M.-F. Xiao, I. Jakovcevski, E. Sivukhina, G. Hargus, Y.-F. Cui, A. Irintchev, M. Schachner, and C. Bernreuther (2014)
J. Cell Sci. 127, 641-652
   Abstract »    Full Text »    PDF »
Cell Type-specific Signaling Function of RhoA GTPase: Lessons from Mouse Gene Targeting.
X. Zhou and Y. Zheng (2013)
J. Biol. Chem. 288, 36179-36188
   Abstract »    Full Text »    PDF »
N-Cadherin Sustains Motility and Polarity of Future Cortical Interneurons during Tangential Migration.
C. Luccardini, L. Hennekinne, L. Viou, M. Yanagida, F. Murakami, N. Kessaris, X. Ma, R. S. Adelstein, R.-M. Mege, and C. Metin (2013)
J. Neurosci. 33, 18149-18160
   Abstract »    Full Text »    PDF »
PTB Deficiency Causes the Loss of Adherens Junctions in the Dorsal Telencephalon and Leads to Lethal Hydrocephalus.
T. Shibasaki, A. Tokunaga, R. Sakamoto, H. Sagara, S. Noguchi, T. Sasaoka, and N. Yoshida (2013)
Cereb Cortex 23, 1824-1835
   Abstract »    Full Text »    PDF »
Specific Conserved C-terminal Amino Acids of Caenorhabditis elegans HMP-1/{alpha}-Catenin Modulate F-actin Binding Independently of Vinculin.
S. L. Maiden, N. Harrison, J. Keegan, B. Cain, A. M. Lynch, J. Pettitt, and J. Hardin (2013)
J. Biol. Chem. 288, 5694-5706
   Abstract »    Full Text »    PDF »
Genome and Transcriptome Sequencing in Prospective Metastatic Triple-Negative Breast Cancer Uncovers Therapeutic Vulnerabilities.
D. W. Craig, J. A. O'Shaughnessy, J. A. Kiefer, J. Aldrich, S. Sinari, T. M. Moses, S. Wong, J. Dinh, A. Christoforides, J. L. Blum, et al. (2013)
Mol. Cancer Ther. 12, 104-116
   Abstract »    Full Text »    PDF »
{alpha}-Catenin Inhibits {beta}-Catenin-T-cell Factor/Lymphoid Enhancing Factor Transcriptional Activity and Collagen Type II Expression in Articular Chondrocytes through Formation of Gli3R{middle dot}{alpha}-Catenin{middle dot}{beta}-Catenin Ternary Complex.
J. Rhee, J.-H. Ryu, J.-H. Kim, C.-H. Chun, and J.-S. Chun (2012)
J. Biol. Chem. 287, 11751-11760
   Abstract »    Full Text »    PDF »
Cadherins in Brain Morphogenesis and Wiring.
S. Hirano and M. Takeichi (2012)
Physiol Rev 92, 597-634
   Abstract »    Full Text »    PDF »
A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin-A.
A. Carabalona, S. Beguin, E. Pallesi-Pocachard, E. Buhler, C. Pellegrino, K. Arnaud, P. Hubert, M. Oualha, J. P. Siffroi, S. Khantane, et al. (2012)
Hum. Mol. Genet. 21, 1004-1017
   Abstract »    Full Text »    PDF »
The secret life of {alpha}-catenin: Moonlighting in morphogenesis.
S. L. Maiden and J. Hardin (2011)
J. Cell Biol. 195, 543-552
   Abstract »    Full Text »    PDF »
{alpha}-Catenin Is a Tumor Suppressor That Controls Cell Accumulation by Regulating the Localization and Activity of the Transcriptional Coactivator Yap1.
M. R. Silvis, B. T. Kreger, W.-H. Lien, O. Klezovitch, G. M. Rudakova, F. D. Camargo, D. M. Lantz, J. T. Seykora, and V. Vasioukhin (2011)
Science Signaling 4, ra33
   Abstract »    Full Text »    PDF »
Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation.
K.-i. Katayama, J. Melendez, J. M. Baumann, J. R. Leslie, B. K. Chauhan, N. Nemkul, R. A. Lang, C.-Y. Kuan, Y. Zheng, and Y. Yoshida (2011)
PNAS 108, 7607-7612
   Abstract »    Full Text »    PDF »
N-cadherin-mediated cell adhesion restricts cell proliferation in the dorsal neural tube.
K. Chalasani and R. M. Brewster (2011)
Mol. Biol. Cell 22, 1505-1515
   Abstract »    Full Text »    PDF »
The Small GTPase RhoA Is Required to Maintain Spinal Cord Neuroepithelium Organization and the Neural Stem Cell Pool.
D. Herzog, P. Loetscher, J. van Hengel, S. Knusel, C. Brakebusch, V. Taylor, U. Suter, and J. B. Relvas (2011)
J. Neurosci. 31, 5120-5130
   Abstract »    Full Text »    PDF »
Oblique Radial Glial Divisions in the Developing Mouse Neocortex Induce Self-Renewing Progenitors outside the Germinal Zone That Resemble Primate Outer Subventricular Zone Progenitors.
A. Shitamukai, D. Konno, and F. Matsuzaki (2011)
J. Neurosci. 31, 3683-3695
   Abstract »    Full Text »    PDF »
An evolutionarily conserved PTEN-C/EBP{alpha}-CTNNA1 axis controls myeloid development and transformation.
C.-T. Fu, K.-Y. Zhu, J.-Q. Mi, Y.-F. Liu, S. T. Murray, Y.-F. Fu, C.-G. Ren, Z.-W. Dong, Y.-J. Liu, M. Dong, et al. (2010)
Blood 115, 4715-4724
   Abstract »    Full Text »    PDF »
{alpha}E-catenin regulates actin dynamics independently of cadherin-mediated cell-cell adhesion.
J. M. Benjamin, A. V. Kwiatkowski, C. Yang, F. Korobova, S. Pokutta, T. Svitkina, W. I. Weis, and W. J. Nelson (2010)
J. Cell Biol. 189, 339-352
   Abstract »    Full Text »    PDF »
Morphogenesis in Kyoto: A Confluence of Cell and Developmental Biology.
J. A. Zallen and A. S. Yap (2010)
Mol. Biol. Cell 21, 845-847
   Abstract »    Full Text »    PDF »
N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38{alpha}/{beta} MAPK signaling in skeletal myoblasts.
M. Lu and R. S. Krauss (2010)
PNAS 107, 4212-4217
   Abstract »    Full Text »    PDF »
FAK-mediated extracellular signals are essential for interkinetic nuclear migration and planar divisions in the neuroepithelium.
S. Tsuda, T. Kitagawa, S. Takashima, S. Asakawa, N. Shimizu, H. Mitani, A. Shima, M. Tsutsumi, H. Hori, K. Naruse, et al. (2010)
J. Cell Sci. 123, 484-496
   Abstract »    Full Text »    PDF »
Adhesive and Signaling Functions of Cadherins and Catenins in Vertebrate Development.
E. Stepniak, G. L. Radice, and V. Vasioukhin (2009)
Cold Spring Harb Perspect Biol 1, a002949
   Abstract »    Full Text »    PDF »
Junctional Music that the Nucleus Hears: Cell-Cell Contact Signaling and the Modulation of Gene Activity.
P. D. McCrea, D. Gu, and M. S. Balda (2009)
Cold Spring Harb Perspect Biol 1, a002923
   Abstract »    Full Text »    PDF »
Structure and Biochemistry of Cadherins and Catenins.
L. Shapiro and W. I. Weis (2009)
Cold Spring Harb Perspect Biol 1, a003053
   Abstract »    Full Text »    PDF »
Mammalian Fat and Dachsous cadherins regulate apical membrane organization in the embryonic cerebral cortex.
T. Ishiuchi, K. Misaki, S. Yonemura, M. Takeichi, and T. Tanoue (2009)
J. Cell Biol. 185, 959-967
   Abstract »    Full Text »    PDF »
Adherens junction domains are split by asymmetric division of embryonic neural stem cells.
V. Marthiens and C. ffrench-Constant (2009)
EMBO Rep. 10, 515-520
   Abstract »    Full Text »    PDF »
E-Cadherin Regulates Neural Stem Cell Self-Renewal.
P. Karpowicz, S. Willaime-Morawek, L. Balenci, B. DeVeale, T. Inoue, and D. van der Kooy (2009)
J. Neurosci. 29, 3885-3896
   Abstract »    Full Text »    PDF »
A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers.
B. Stecca and A. Ruiz i Altaba (2009)
EMBO J. 28, 663-676
   Abstract »    Full Text »    PDF »
{alpha}-E-catenin binds to dynamitin and regulates dynactin-mediated intracellular traffic.
W.-H. Lien, V. I. Gelfand, and V. Vasioukhin (2008)
J. Cell Biol. 183, 989-997
   Abstract »    Full Text »    PDF »
Single-cell gene profiling defines differential progenitor subclasses in mammalian neurogenesis.
A. Kawaguchi, T. Ikawa, T. Kasukawa, H. R. Ueda, K. Kurimoto, M. Saitou, and F. Matsuzaki (2008)
Development 135, 3113-3124
   Abstract »    Full Text »    PDF »
Hedgehog signaling is involved in development of the neocortex.
M. Komada, H. Saitsu, M. Kinboshi, T. Miura, K. Shiota, and M. Ishibashi (2008)
Development 135, 2717-2727
   Abstract »    Full Text »    PDF »
{alpha}E-catenin is not a significant regulator of {beta}-catenin signaling in the developing mammalian brain.
W.-H. Lien, O. Klezovitch, M. Null, and V. Vasioukhin (2008)
J. Cell Sci. 121, 1357-1362
   Abstract »    Full Text »    PDF »
Neural stem cells: balancing self-renewal with differentiation.
C. Q. Doe (2008)
Development 135, 1575-1587
   Abstract »    Full Text »    PDF »
Instructive role of aPKC{zeta} subcellular localization in the assembly of adherens junctions in neural progenitors.
S. Ghosh, T. Marquardt, J. P. Thaler, N. Carter, S. E. Andrews, S. L. Pfaff, and T. Hunter (2008)
PNAS 105, 335-340
   Abstract »    Full Text »    PDF »
N-cofilin is associated with neuronal migration disorders and cell cycle control in the cerebral cortex.
G. C. Bellenchi, C. B. Gurniak, E. Perlas, S. Middei, M. Ammassari-Teule, and W. Witke (2007)
Genes & Dev. 21, 2347-2357
   Abstract »    Full Text »    PDF »
Cell-Autonomous beta-Catenin Signaling Regulates Cortical Precursor Proliferation.
G. J. Woodhead, C. A. Mutch, E. C. Olson, and A. Chenn (2006)
J. Neurosci. 26, 12620-12630
   Abstract »    Full Text »    PDF »
Re-solving the Cadherin-Catenin-Actin Conundrum.
W. I. Weis and W. J. Nelson (2006)
J. Biol. Chem. 281, 35593-35597
   Full Text »    PDF »
Cinderella no longer: {alpha}-catenin steps out of cadherin's shadow.
J. A. Scott and A. S. Yap (2006)
J. Cell Sci. 119, 4599-4605
   Abstract »    Full Text »    PDF »
Hedgehog signaling and the retina: insights into the mechanisms controlling the proliferative properties of neural precursors..
M. Locker, M. Agathocleous, M. A. Amato, K. Parain, W. A. Harris, and M. Perron (2006)
Genes & Dev. 20, 3036-3048
   Abstract »    Full Text »    PDF »
Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly.
L. Chen, G. Liao, L. Yang, K. Campbell, M. Nakafuku, C.-Y. Kuan, and Y. Zheng (2006)
PNAS 103, 16520-16525
   Abstract »    Full Text »    PDF »
Hedgehog makes giant brains.
N. LeBrasseur (2006)
J. Cell Biol. 173, 5a
   Full Text »    PDF »
NEUROSCIENCE: Enhanced: Neuron, Know Thy Neighbor.
E. DiCicco-Bloom (2006)
Science 311, 1560-1562
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882