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Cited by 3dental development and anomaliesDevelopmental Biology and Gene RegulationCleft Lip and Palate Research

Wolf-Hirschhorn syndrome candidate 1 (Whsc1) methyltransferase signals via a Pitx2-miR-23/24 axis to effect tooth development

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Su, Dan, Eliason, Steve, Sun, Zhao, Shao, Fan, Amendt, Brad A.·2023·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2023.105324PMC PMC10656234
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Abstract

Wolf-Hirschhorn syndrome (WHS) is a developmental disorder attributed to a partial deletion on the short arm of chromosome 4. WHS patients suffer from oral manifestations including cleft lip and palate, hypodontia, and taurodontism. WHS candidate 1 (WHSC1) gene is a H3K36-specific methyltransferase that is deleted in every reported case of WHS. Mutation in this gene also results in tooth anomalies in patients. However, the correlation between genetic abnormalities and the tooth anomalies has remained controversial. In our study, we aimed to clarify the role of WHSC1 in tooth development. We profiled the Whsc1 expression pattern during mouse incisor and molar development by immunofluorescence staining and found Whsc1 expression is reduced as tooth development proceeds. Using real-time quantitative reverse transcription PCR, Western blot, chromatin immunoprecipitation, and luciferase assays, we determined that Whsc1 and Pitx2, the initial transcription factor involved in tooth development, positively and reciprocally regulate each other through their gene promoters. miRNAs are known to regulate gene expression posttranscriptionally during development. We previously reported miR-23a/b and miR-24-1/2 were highly expressed in the mature tooth germ. Interestingly, we demonstrate here that these two miRs directly target Whsc1 and repress its expression. Additionally, this miR cluster is also negatively regulated by Pitx2. We show the expression of these two miRs and Whsc1 are inversely correlated during mouse mandibular development. Taken together, our results provide new insights into the potential role of Whsc1 in regulating tooth development and a possible molecular mechanism underlying the dental defects in WHS.

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  • The impact of miR-23 on organisms is long-lasting and can affect tooth growth during embryonic stages.

    “The studies provide evidences that the impact of miR-23 on organisms is long-lasting and can affect tooth growth during embryonic stages.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [119]

    The Results section (page unavailable) reports that miR-23a/b expression increases across embryonic stages of mouse tooth development and suggests that it regulates Whsc1 during that period. The Discussion (page unavailable) also describes a role for miR-23a/b in tooth-cell differentiation. Neither passage establishes a long-lasting effect on organisms, so that part of the claim is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Expression of miR-23 in mouse embryos leads to a decrease in Hmgn2, which subsequently boosts amelogenin expression through multiple transcription factors including Pitx2, Dlx2, Lef-1, and FoxJ1.

    “The expression of miR-23 in mouse embryos leads to a decrease in Hmgn2, which subsequently boosts the amelogenin expression through multiple transcription factors, including Pitx2, Dlx2, Lef-1, and FoxJ1 [118,119].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [119]

    The Discussion section “Whsc1 expression is controlled by miRNAs” (page unavailable) says miR-23a/b targets Hmgn2 and that Hmgn2 prevents transcription factors from activating gene expression. The copy does not establish that this pathway boosts amelogenin expression through all four named factors, or demonstrate the claimed effect in mouse embryos. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • miR-23a/b are highly expressed in mature tooth germ, and they share common target genes Hmgn2 and Whsc1.

    “miR-23a/b are highly expressed in mature tooth germ, and they share common target genes, namely high mobility group protein N2 (Hmgn2), and Wolf-Hirschhorn syndrome candidate 1 gene (Whsc1).”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [119]

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References 87 · Cited by 3

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Authors
Su, D., Eliason, S., Sun, Z., Shao, F., & Amendt, B. A.
Affiliations
  • University of Iowa (US)
  • Washington University in St. Louis (US)
Corresponding author
Amendt, Brad A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2023-11
Volume
299
Issue
11
Pages
105324
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2023.105324
PMC
PMC10656234
OpenAlex
W4387394498
Cited by
3
References
87
Citations by year
2026: 1 · 2025: 1 · 2024: 1
FWCI
0.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • NIDCR (DE028527)
  • University of Iowa
  • National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Cleft Lip and Palate Research
Keywords
Wolf-Hirschhorn syndrome, WHSC1, PITX2, microRNA-24, tooth development, tooth germ, tooth agenesis, taurodontism, cleft lip and palate, gene expression regulation, chromatin modification
MeSH terms
Homeobox Protein PITX2, Animals, Cleft Lip, Cleft Palate, Histone-Lysine N-Methyltransferase, Transcription Factors, MicroRNAs, Mice, Wolf-Hirschhorn Syndrome

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