Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms

  1. Parthiv Haldipur
  2. Derek Dang
  3. Kimberly A Aldinger
  4. Olivia K Janson
  5. Fabien Guimiot
  6. Homa Adle-Biasette
  7. William B Dobyns
  8. Joseph R Siebert
  9. Rosa Russo
  10. Kathleen J Millen  Is a corresponding author
  1. Seattle Children's Research Institute, United States
  2. SCRI, United States
  3. Seattle Chidren's Research Institute, United States
  4. INSERM UMR 1141, France
  5. Seattle Children's Hospital, United States
  6. S. Giovanni di Dio e Ruggi D'Aragona, Italy

Abstract

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation.  Previously we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule echoing the posterior vermis DW "tail sign" observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.

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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. Derek Dang

    CIBR, SCRI, SEATTLE, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kimberly A Aldinger

    CIBR, SCRI, SEATTLE, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
  5. Fabien Guimiot

    Hôpital Robert-Debré, INSERM UMR 1141, PARIS, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Homa Adle-Biasette

    Hôpital Robert-Debré, INSERM UMR 1141, PARIS, France
    Competing interests
    The authors declare that no competing interests exist.
  7. William B Dobyns

    CIBR, SCRI, SEATTLE, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Joseph R Siebert

    pathology, Seattle Children's Hospital, seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rosa Russo

    University Medical College, S. Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9978-675X

Funding

National Institutes of Health (R01NS072441)

  • Kathleen J Millen

National Institutes of Health (R01NS080390)

  • Kathleen J Millen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experimentation for this study was approved by the Institutional Animal Care and Use Committee (IACUC Protocol no 14208), of Seattle Children's Research Institute, Seattle, WA, USA..

Human subjects: All human studies were approved by Institutional Review Boards at all participating institutions. Written informed consent was obtained from all subjects.

Reviewing Editor

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

Publication history

  1. Received: August 23, 2016
  2. Accepted: January 15, 2017
  3. Accepted Manuscript published: January 16, 2017 (version 1)
  4. Version of Record published: January 27, 2017 (version 2)

Copyright

© 2017, 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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  1. Parthiv Haldipur
  2. Derek Dang
  3. Kimberly A Aldinger
  4. Olivia K Janson
  5. Fabien Guimiot
  6. Homa Adle-Biasette
  7. William B Dobyns
  8. Joseph R Siebert
  9. Rosa Russo
  10. Kathleen J Millen
(2017)
Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms
eLife 6:e20898.
https://doi.org/10.7554/eLife.20898
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