Journal article
Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation
Developmental biology, Vol.458(2), pp.246-256
02/15/2020
DOI: 10.1016/j.ydbio.2019.11.010
PMCID: PMC7568837
PMID: 31765609
Abstract
In this study, we investigated the role of the transcription factor Six2 in palate development. Six2 was selected using the SysFACE tool to predict genes from the 2p21 locus, a region associated with clefting in humans by GWAS, that are likely to be involved in palatogenesis. We functionally validated the predicted role of Six2 in palatogenesis by showing that 22% of Six2 null embryos develop cleft palate. Six2 contributes to palatogenesis by promoting mesenchymal cell proliferation and regulating bone formation. The clefting phenotype in Six2(-/-) embryos is similar to Pax9 null embryos, so we examined the functional relationship of these two genes. Mechanistically, SIX2 binds to a PAX9 5' upstream regulatory element and activates PAX9 expression. In addition, we identified a human SIX2 coding variant (p.Gly264Glu) in a proband with cleft palate. We show this missense mutation affects the stability of the SIX2 protein and leads to decreased PAX9 expression. The low penetrance of clefting in the Six2 null mouse combined with the mutation in one patient with cleft palate underscores the potential combinatorial interactions of other genes in clefting. Our study demonstrates that Six2 interacts with the developmental gene regulatory network in the developing palate.
Details
- Title: Subtitle
- Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation
- Creators
- Yan Yan Sweat - University of IowaMason Sweat - University of IowaMaurisa Mansaray - University of IowaHuojun Cao - University of IowaSteven Eliason - University of IowaWaisu L. Adeyemo - University of LagosLord J. J. Gowans - Kwame Nkrumah University of Science and TechnologyMekonen A. Eshete - Addis Ababa UniversityDeepti Anand - University of DelawareCamille Chalkley - University of IowaIrfan Saadi - University of Kansas Medical CenterSalil A. Lachke - University of DelawareAzeez Butali - University of IowaBrad A. Amendt - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Developmental biology, Vol.458(2), pp.246-256
- DOI
- 10.1016/j.ydbio.2019.11.010
- PMID
- 31765609
- PMCID
- PMC7568837
- NLM abbreviation
- Dev Biol
- ISSN
- 0012-1606
- eISSN
- 1095-564X
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- R03DE024776; R01DE026172; DE026433; DE023520 / NIDCR; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR) University of Iowa Carver College of Medicine and College of Dentistry
- Language
- English
- Date published
- 02/15/2020
- Academic Unit
- Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Endodontics; Stead Family Department of Pediatrics; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984284352702771
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