title: Phenotypic outcomes in Mouse and HumanFoxc1dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.
abstract: FOXC1loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that completeFoxc1loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphicFoxc1mutant 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 inFoxc1mutant 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 ourFoxc1mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Parthiv
authors.initials: P
authors.lastname: Haldipur
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Dang
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Aldinger
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Olivia K
authors.initials: OK
authors.lastname: Janson
authors.affiliation: Hôpital Robert-Debré, INSERM UMR 1141, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guimiot
authors.affiliation: Hôpital Robert-Debré, INSERM UMR 1141, Paris, France.
authors.forename: Homa
authors.initials: H
authors.lastname: Adle-Biasette
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.|Department of Pediatrics, Genetics Division, University of Washington, Seattle, United States.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Department of Laboratories, Seattle Children's Hospital, Seattle, United States.|Department of Pathology, University of Washington, Seattle, United States.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Siebert
authors.affiliation: Department of Pathology, Molecular Genetics Laboratory, University Medical Hospital, Salerno, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Russo
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.|Department of Pediatrics, Genetics Division, University of Washington, Seattle, United States.
authors.forename: Kathleen J
authors.identifier: 0000-0001-9978-675X
authors.initials: KJ
authors.lastname: Millen
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002465:Cell Movement; D003616:Dandy-Walker Syndrome / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D051379:Mice
chemical_list: C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse
keywords: Dandy-Walker; brain; cerebellum; development; developmental biology; human; mouse; neuroscience; stem cells