1. Developmental Biology
  2. Neuroscience
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Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth

  1. Parthiv Haldipur
  2. Gwendolyn S Gillies
  3. Olivia K Janson
  4. Victor V Chizhikov
  5. Divakar S Mithal
  6. Richard J Miller
  7. Kathleen J Millen  Is a corresponding author
  1. Seattle Children's Research Institute, United States
  2. Seattle Chidren's Research Institute, United States
  3. University of Tennessee Health Sciences Center, United States
  4. Northwestern University, United States
Research Article
  • Cited 25
  • Views 2,094
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Cite this article as: eLife 2014;3:e03962 doi: 10.7554/eLife.03962

Abstract

Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1-/- cerebellar phenotype. SDF1α also rescues the Foxc1-/- phenotype. Our data emphasizes that head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans.

Article and author information

Author details

  1. Parthiv Haldipur

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Gwendolyn S Gillies

    Center for Integrative Brain Research, Seattle Chidren's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Olivia K Janson

    Center for Integrative Brain Research, Seattle Chidren's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Victor V Chizhikov

    Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Divakar S Mithal

    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Richard J Miller

    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kathleen J Millen

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    For correspondence
    kathleen.millen@seattlechildrens.org
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal experimentation done in this study was done in accordance with the guidelines laid down by the Institutional Animal Care and Use Committee (IACUC), of Seattle Children's Research Institute (protocol# 14208), Seattle, WA, USA.

Reviewing Editor

  1. Robb Krumlauf, Stowers Institute for Medical Research, United States

Publication history

  1. Received: July 10, 2014
  2. Accepted: December 16, 2014
  3. Accepted Manuscript published: December 16, 2014 (version 1)
  4. Version of Record published: January 2, 2015 (version 2)

Copyright

© 2014, Haldipur et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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