Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation

Sweat, Yan Yan; Sweat, Mason; Mansaray, Maurisa; Cao, Huojun; Eliason, Steven; Adeyemo, Waisu L.; Gowans, Lord Jephthah Joojo; Eshete, Mekonen; Anand, Deepti; Chalkley, Camille; Saadi, Irfan; Lachke, Salil A.; Butali, Azeez; Amendt, Brad A.

doi:10.1016/j.ydbio.2019.11.010

Cited by 16 publications

(12 citation statements)

References 48 publications

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“…Therefore, in the present study, we selected the target region of the haplotype around rs7590268 for sequencing in the hope of gaining novel insights into the 2p21 locus. Notably, our results indicated that ZFP36L2 in 2p21 locus is a susceptibility gene for NSCLO, whereas the previous study only identified ZFP36L2 and SIX2 in 2p21 locus to be associated with NSCL/P and NSCPO, respectively (Lin-Shiao et al, 2019;Sweat et al, 2020).…”

Section: Discussioncontrasting

confidence: 80%

Targeted Re-Sequencing of the 2p21 Locus Identifies Non-Syndromic Cleft Lip Only Novel Susceptibility Gene ZFP36L2

Shi

Zhu

et al. 2022

Front. Genet.

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rs7590268 present on the 2p21 locus was identified to be associated with non-syndromic cleft lip with or without cleft palate (NSCL/P) in several populations, including the Chinese Han population, indicating that 2p21 was a susceptibility locus for NSCL/P. However, previous studies have only identified common single-nucleotide polymorphism (SNP) within the THADA gene, neglecting the rare variants and other genes in 2p21; thus, this study was designed to investigate additional variants and novel susceptibility genes in 2p21. A total of 159 NSCL/P patients and 542 controls were recruited in the discovery phase, whereas 1830 NSCL/P patients and 2,436 controls were recruited in the replication phase. After targeted region sequencing, we performed association and burden analyses for the common and rare variants, respectively. Furthermore, RNA-seq, proliferation assay and cell cycle analysis were performed to clarify the possible function of the candidate gene ZFP36L2. Association analysis showed that four SNPs were specifically associated with non-syndromic cleft lip only (NSCLO) and two SNPs were associated with both NSCLO and NSCL/P. Burden analysis indicated that ZFP36L2 was associated with NSCLO (p = .0489, OR = 2.41, 95% CI: 0.98–5.90). Moreover, SNPs in the ZFP36L2 targeted gene JUP were also associated with NSCLO. ZFP36L2 also inhibited cell proliferation and induced G2 phase arrest in the GMSM-K cell line. Therefore, we proposed that ZFP36L2 is a novel susceptibility gene of NSCLO in the 2p21 locus, which could lead to NSCLO by modulating cell proliferation and cycle.

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Section: Discussioncontrasting

confidence: 80%

Targeted Re-Sequencing of the 2p21 Locus Identifies Non-Syndromic Cleft Lip Only Novel Susceptibility Gene ZFP36L2

Shi

Zhu

et al. 2022

Front. Genet.

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“…Regulation of PAX9 expression has been extensively studied in embryonic development, in particular, craniofacial and tooth development. Several molecular pathways and transcription factors, for example, GLI3 and SHH [ 42 ], BMP [ 43 ], SIX2 [ 44 ], and FGF [ 45 ], were found to control PAX9 expression during embryonic development. It remains unknown whether these molecular pathways or genes may regulate PAX9 expression in specific cancers.…”

Section: Upstream Regulation Of Pax9 Expressionmentioning

confidence: 99%

PAX9 in Cancer Development

Chen

Paiboonrungruang

et al. 2022

IJMS

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Paired box 9 (PAX9) is a transcription factor of the PAX family functioning as both a transcriptional activator and repressor. Its functional roles in the embryonic development of various tissues and organs have been well studied. However, its roles and molecular mechanisms in cancer development are largely unknown. Here, we review the current understanding of PAX9 expression, upstream regulation of PAX9, and PAX9 downstream events in cancer development. Promoter hypermethylation, promoter SNP, microRNA, and inhibition of upstream pathways (e.g., NOTCH) result in PAX9 silencing or downregulation, whereas gene amplification and an epigenetic axis upregulate PAX9 expression. PAX9 may contribute to carcinogenesis through dysregulation of its transcriptional targets and related molecular pathways. In summary, extensive studies on PAX9 in its cellular and tissue contexts are warranted in various cancers, in particular, HNSCC, ESCC, lung cancer, and cervical SCC.

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“…Alternatively, it could be failure of the opposing shelves to fuse at the midline when the leading-edge epithelia met, with subsequent growth of the head causing a relative retraction of the shelves that left the gap. Analyses of mutant mouse models indicate that developmental regulation of mesenchymal cell proliferation, palate shelf elongation, and fusion at the medial epithelial seam involves multiple signaling pathways, including sonic hedgehog (SHH), wingless-related integration site (WNT), broblast growth factor (FGF), bone morphogenic protein (BMP), and transforming growth factor β (TGFβ), and that there is extensive cross-regulation between pathways (Gritli-Linde 2007; Lan and Jiang 2009; Iwata et al 2011; Lane and Kaartinen 2014; Okello et al 2017;Jia et al 2017;Reynolds et al 2019;Sweat et al 2020). We note that some of the same signaling pathways that affect palate development are involved in limb development (e.g.…”

Section: Discussionmentioning

confidence: 99%

Non-Syndromic Cleft Palate and Transverse Limb Deficiency Segregating in a Family of Dogs

Fyfe¹,

Mahmood²,

Hix³

et al. 2021

Preprint

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Oro-facial clefts are one of the most common birth defects in humans, most are non-syndromic, and few have established molecular diagnoses. Here we report the morphology and genetic transmission of isolated cleft palate in a naturally occurring dog model. Palate morphology was evaluated grossly, by microcomputed tomography, and by histologic examination of serial coronal sections. In repeated matings of a clinically normal sire/dam pair, 18% (12/68) of live-born pups had full-length cleft of the secondary palate with no other abnormalities. At the gestational stage of normal palate fusion, palate shelves of affected fetuses were above the tongue but did not meet at midline. Mandibles were normal, and oral epithelium and periderm were intact. Genetic transmission was determined in experimental backcross matings of surgically repaired affected dogs with a normal parent, which produced 20 cleft, 11 male and 9 female, and 24 normal-palate pups. Furthermore, all offspring of matings between affected dogs had cleft palate. These data were as expected under the hypothesis of autosomal recessive transmission of the cleft palate trait ([1 df, N = 44] Χ2 = 0.36, p = 0.55). About half of cleft offspring produced in backcross matings of which the dam had cleft palate, also exhibited various transverse limb deficiencies. No limb deficiencies occurred in backcross offspring of a dam with normal palate, suggesting a possible maternal effect. This dog family constitutes a large animal model of non-syndromic isolated cleft palate coincident with developmental limb deficiency.

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Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation

Cited by 16 publications

References 48 publications

Targeted Re-Sequencing of the 2p21 Locus Identifies Non-Syndromic Cleft Lip Only Novel Susceptibility Gene ZFP36L2

Targeted Re-Sequencing of the 2p21 Locus Identifies Non-Syndromic Cleft Lip Only Novel Susceptibility Gene ZFP36L2

PAX9 in Cancer Development

Non-Syndromic Cleft Palate and Transverse Limb Deficiency Segregating in a Family of Dogs

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