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

Parthiv Haldipur, Derek Dang, Kimberly A. Aldinger, Olivia K. Janson, Fabien Guimiot, Homa Adle-Biasette, William B. Dobyns, Joseph R. Siebert, Rosa Russo, Kathleen J. Millen

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15 Scopus citations


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 which echoes the posterior vermis DW ‘tail sign’ observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that 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.

Original languageEnglish (US)
Article numbere20898
StatePublished - Jan 16 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Tom Kume (Northwestern University, Chicago, IL) and Samuel J Pleasure (UCSF) for providing us with the Foxc1-/- and Foxc1hith/hith mouse strains respectively. We also gratefully acknowledge the technical assistance of Joanna Yeung, Arianna Gomez, Conrad Winter, and Gwen- dolyn S Gillies. We thank Dr. Alexandra J Joyner (Sloan-Kettering Memorial Hospital, New York) and Dr. Raj Kapur (Seattle Children?s Hospital) for valuable discussions. The work described herein was supported by National Institutes of Health R01NS072441 and R01NS080390 to KJM. All co-authors have seen and agreed to the contents of this manuscript. None of the co-authors have any potential financial interests or conflict of interest with respect to this manuscript. National Institutes of Health R01NS072441 Kathleen J Millen National Institutes of Health R01NS080390 Kathleen J Millen

Publisher Copyright:
© Haldipur et al.

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