Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis
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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.
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We find HF regulatory SNCs in ZIC1 and ZIC4.
“HF regulatory SNCs in ZIC1 and ZIC486”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [86]
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- 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
- Publisher
- The Company of Biologists
- Published
- 2011-03-15
- Volume
- 138
- Issue
- 6
- Pages
- 1207-1216
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC3042874
- 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
- bronze
- doi.org
- 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
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