Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms
- Seattle Children's Research Institute, United States
- SCRI, United States
- Seattle Chidren's Research Institute, United States
- INSERM UMR 1141, France
- Seattle Children's Hospital, United States
- 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.
Article and author information
Author details
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.
Reviewing Editor
- Robb Krumlauf, Stowers Institute for Medical Research, United States
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.
Version history
- Received: August 23, 2016
- Accepted: January 15, 2017
- Accepted Manuscript published: January 16, 2017 (version 1)
- 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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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
Further reading
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