A spontaneous and novel Pax3 mutant mouse that models Waardenburg syndrome and neural tube defects

Ohnishi, Tetsuo; Miura, Ikuo; Ohba, Hideki; Shimamoto, Chie; Iwayama, Yoshimi; Wakana, Shigeharu; Yoshikawa, Takeo

doi:10.1016/j.gene.2016.12.037

Cited by 11 publications

(12 citation statements)

References 9 publications

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“… ), were present from E14.5 to E17.5. The phenotype of the malformed embryos was similar to those described for other Pax3 mutants, such as Pax3 Sp , Pax3 Sp-1H , Pax3 Sp-2H , Pax3 Sp-1Xzg , Pax3 Sp-1Wli , and Pax3 Rwa [ 2 , 5 , 6 , 7 , 10 , 14 ]. There was an extremely small number of homozygous (C3H/C3H) embryos, and litter size tended to be reduced, with the occasional occurrence of fetal death (data not shown) at E17.5.…”

Section: Resultssupporting

confidence: 75%

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A new missense mutation in the paired domain of the mouse <i>Pax3</i> gene

et al. 2017

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Mice with dominant white spotting occurred spontaneously in the C3.NSY-(D11Mit74-D11Mit229) strain. Linkage analysis indicated that the locus for white spotting was located in the vicinity of the Pax3 gene on chromosome 1. Crosses of white-spotted mice showed that homozygosity for the mutation caused tail and limb abnormalities and embryonic lethality as a result of exencephaly; these phenotypes were analogous to those found in other Pax3 mutants. Sequence analysis identified a missense point mutation (c.101G>A) in exon 2 of Pax3 that resulted in a methionine to isoleucine conversion at amino acid 62 of the PAX3 protein. This mutation site was located in the N-terminal HTH (helix-turn-helix) motif of the paired domain of Pax3, which is necessary for binding to DNA and is highly conserved in vertebrate species. Alteration of DNA binding affinity was responsible for embryonic lethality in homozygotes and white spotting in heterozygotes. We named the mutant allele as Pax3Sp-Nag. The C3H/HeN-Pax3Sp-Nag strain may be useful for analyzing the function of Pax3 as a new model of the human disease, Waardenburg Syndrome.

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Section: Resultssupporting

confidence: 75%

“…The looped tail feature was not passed on to the next generation. Although the cause is not known, a similar phenomenon has been reported for other Pax3 mutant mice such as Pax3 Sp-1H , Pax3 Sp-1Xzg , and Pax3 Rwa [ 6 , 10 , 14 ]. Heterozygous ( Pax3 Sp-Nag /+) mice with the p.Met62Ile mutation do not appear to show deafness.…”

Section: Discussionsupporting

confidence: 60%

A new missense mutation in the paired domain of the mouse <i>Pax3</i> gene

et al. 2017

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“…Review of the top doubly significant genes and significant GO terms (i.e. neurogenesis) revealed several genes of particular interest (Table 1), five of which encode transcription factors (Tfap2b, Pax3, Zic5, Tbx3 and Nkx6-1) that control neuronal or glial cell fate [28][29][30][31][32][33][34] . Another gene, Stmn2, was downregulated in Chd7 Gt/Gt cells and encodes a stathmin protein family member that promotes neuronal growth 35 .…”

Section: Chd7 Regulates Genes Expression Chd7 Enrichment In the Genementioning

confidence: 99%

CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression

Yao

Hannum

Zhai

et al. 2020

Sci Rep

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CHARGE syndrome, a rare multiple congenital anomaly condition, is caused by haploinsufficiency of the chromatin remodeling protein gene CHD7 (Chromodomain helicase DNA binding protein 7). Brain abnormalities and intellectual disability are commonly observed in individuals with CHARGE, and neuronal differentiation is reduced in CHARGE patient-derived iPSCs and conditional knockout mouse brains. However, the mechanisms of CHD7 function in nervous system development are not well understood. In this study, we asked whether CHD7 promotes gene transcription in neural progenitor cells via changes in chromatin accessibility. We used Chd7 null embryonic stem cells (ESCs) derived from Chd7 mutant mouse blastocysts as a tool to investigate roles of CHD7 in neuronal and glial differentiation. Loss of Chd7 significantly reduced neuronal and glial differentiation. Sholl analysis showed that loss of Chd7 impaired neuronal complexity and neurite length in differentiated neurons. Genome-wide studies demonstrated that loss of Chd7 leads to modified chromatin accessibility (ATAC-seq) and differential nascent expression (Bru-Seq) of neural-specific genes. These results suggest that CHD7 acts preferentially to alter chromatin accessibility of key genes during the transition of NPCs to neurons to promote differentiation. Our results form a basis for understanding the cell stage-specific roles for CHD7-mediated chromatin remodeling during cell lineage acquisition.

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“…The tail is considered an extension of the spinal column usually composed of specifically shaped vertebrae. Spontaneous curly tail phenotypes in mice have been the matter of studies that investigated the role of embryonic development in this morphological anomaly (Copp et al, 1988;van Straaten and Copp, 2001;Ohnishi et al, 2017). Curly tail is also commonly observed in many dog breeds.…”

Section: Introductionmentioning

confidence: 99%

Exploiting phenotype diversity in a local animal genetic resource: Identification of a single nucleotide polymorphism associated with the tail shape phenotype in the autochthonous Casertana pig breed

et al. 2018

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show abstract

A spontaneous and novel Pax3 mutant mouse that models Waardenburg syndrome and neural tube defects

Cited by 11 publications

References 9 publications

A new missense mutation in the paired domain of the mouse <i>Pax3</i> gene

A new missense mutation in the paired domain of the mouse <i>Pax3</i> gene

CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression

Exploiting phenotype diversity in a local animal genetic resource: Identification of a single nucleotide polymorphism associated with the tail shape phenotype in the autochthonous Casertana pig breed

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