Cited by 116Fetal and Pediatric Neurological DisordersNeurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene Regulation

Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis

Open access
Blank, Marissa C., Grinberg, Inessa, Aryee, Emmanuel, Laliberte, Christine, Chizhikov, Victor V., Henkelman, R. Mark, Millen, Kathleen J.·2011·Development

Abstract

Heterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. Through genetic and molecular analyses, we show that Zic1 and Zic4 have Shh-dependent function promoting proliferation of granule cell progenitors. Expression of the Shh-downstream genes Ptch1, Gli1 and Mycn was downregulated in Zic1/4 mutants, although Shh production and Purkinje cell gene expression were normal. Reduction of Shh dose on the Zic1+/−;Zic4+/− background also resulted in cerebellar size reductions and gene expression changes comparable with those observed in Zic1−/−;Zic4−/− mice. Zic1 and Zic4 are additionally required to pattern anterior vermis foliation. Zic mutant folial patterning abnormalities correlated with disrupted cerebellar anlage gene expression and Purkinje cell topography during late embryonic stages; however, this phenotype was Shh independent. In Zic1+/−;Zic4+/−;Shh+/−, we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo-cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1242/dev.054114

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Blank, M. C., Grinberg, I., Aryee, E., Laliberte, C., Chizhikov, V. V., Henkelman, R. M., & Millen, K. J.
Affiliations
  • University of Chicago (US)
  • The Mouse Imaging Centre (MICE), SickKids, 25 Orde Street, Toronto, ON M5T 3H7, Canada
  • Seattle Children's Hospital (US)
  • Hospital for Sick Children (CA)
Corresponding author
Millen, Kathleen J.
Venue
Development
Published
2011-03-15
Volume
138
Issue
6
Pages
1207-1216
ISSN
  • 0950-1991 (ISSN-L)
  • 1477-9129
OpenAlex
W2171887429
Cited by
116
References
47
Citations by year
2026: 8 · 2025: 13 · 2024: 13 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 6 · 2016: 1 · 2015: 11 · 2014: 5 · 2013: 11 · 2012: 8
FWCI
7.36
Type
journal article
Language
en
Open access
Locations
  • Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (T32GM007183)
  • National Institute of Neurological Disorders and Stroke (R01NS072441, R01NS050386)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Dandy-Walker malformation, ZIC1, ZIC4, cerebellar development, cerebellar foliation, Sonic hedgehog signaling, GLI2, SMO, PTCH1, Gli1, MYCN, congenital malformations
MeSH terms
Animals, Animals, Newborn, Cerebellum, Dandy-Walker Syndrome, Embryo, Mammalian, Female, Humans, Organ Size, Pregnancy, Transcription Factors, Mice, Knockout, Homeodomain Proteins, Gene Expression Regulation, Developmental, Cell Proliferation, Mice, Hedgehog Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review