Effects of retinoic acid on proliferation and gene expression of cleft and non-cleft palatal keratinocytes

Mammadova, Aysel; Ackermans, Mignon M G; Bloemen, Marjon; Oostendorp, Corien; Zhou, Huiqing; Carels, Carine; Hoff, Johannes W. Von den

doi:10.1093/ejo/cjt104

Cited by 5 publications

(6 citation statements)

References 46 publications

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“…While previous studies have shown the importance of neural crest cells in CL/P development (14), different tissue systems are expected to contribute to this complex disease. In particular, keratinocytes from patients with CL/P have recently been reported to display differentiation defects (48)(49)(50)(51). On the basis of the key observation that p63 + KLF4 establish enhancers to regulate keratinocyte-specific genes, including critical craniofacial genes (see fig.…”

Section: P63 Regulates Expression Of Critical Genes Associated With C...mentioning

confidence: 99%

p63 establishes epithelial enhancers at critical craniofacial development genes

Lin-Shiao

Lan²,

Welzenbach

et al. 2019

Sci. Adv.

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The transcription factor p63 is a key mediator of epidermal development. Point mutations in p63 in patients lead to developmental defects, including orofacial clefting. To date, knowledge on how pivotal the role of p63 is in human craniofacial development is limited. Using an inducible transdifferentiation model, combined with epigenomic sequencing and multicohort meta-analysis of genome-wide association studies data, we show that p63 establishes enhancers at craniofacial development genes to modulate their transcription. Disease-specific substitution mutation in the DNA binding domain or sterile alpha motif protein interaction domain of p63, respectively, eliminates or reduces establishment of these enhancers. We show that enhancers established by p63 are highly enriched for single-nucleotide polymorphisms associated with nonsyndromic cleft lip ± cleft palate (CL/P). These orthogonal approaches indicate a strong molecular link between p63 enhancer function and CL/P, illuminating molecular mechanisms underlying this developmental defect and revealing vital regulatory elements and new candidate causative genes.

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Section: P63 Regulates Expression Of Critical Genes Associated With C...mentioning

confidence: 99%

p63 establishes epithelial enhancers at critical craniofacial development genes

Lin-Shiao

Lan²,

Welzenbach

et al. 2019

Sci. Adv.

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“…Vitamin A is acquired through products such as meat, milk, eggs and carrots (Metzler and Sandell, 2016). Vitamin A deficiency (serum level < 0.70 µmol/L) is a public health concern in countries in Africa and South East Asia, and was associated with craniofacial malformations including CLP (WHO 4 ) (Ackermans et al, 2011;Mammadova et al, 2014;Metzler and Sandell, 2016;Williams and Bohnsack, 2019). Supplementation with vitamin A was associated with a lower cleft risk (OR = 0.48) (Johansen et al, 2008).…”

Section: Vitamin Amentioning

confidence: 99%

Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors

Raterman

Metz

Wagener

et al. 2020

Front. Cell Dev. Biol.

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The zebrafish is an appealing model organism for investigating the genetic (G) and environmental (E) factors, as well as their interactions (GxE), which contribute to craniofacial malformations. Here, we review zebrafish studies on environmental factors involved in the etiology of craniofacial malformations in humans including maternal smoking, alcohol consumption, nutrition and drug use. As an example, we focus on the (cleft) palate, for which the zebrafish ethmoid plate is a good model. This review highlights the importance of investigating ExE interactions and discusses the variable effects of exposure to environmental factors on craniofacial development depending on dosage, exposure time and developmental stage. Zebrafish also promise to be a good tool to study novel craniofacial teratogens and toxin mixtures. Lastly, we discuss the handful of studies on gene–alcohol interactions using mutant sensitivity screens and reverse genetic techniques. We expect that studies addressing complex interactions (ExE and GxE) in craniofacial malformations will increase in the coming years. These are likely to uncover currently unknown mechanisms with implications for the prevention of craniofacial malformations. The zebrafish appears to be an excellent complementary model with high translational value to study these complex interactions.

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“…RA treatment of pregnant rats causes impaired shelf adhesion (Choi et al, 2011). Interestingly, RA treatment also decreases the proliferation of human palatal epithelial cells in vitro (Mammadova et al, 2014) as well as their differentiation (unpublished data). RA also increases apoptosis in the midline edge epithelium (Choi et al, 2011;Cuervo et al, 2002).…”

Section: Ra In the Development Of Craniofacial Structures: The Second...mentioning

confidence: 82%

“…RA downregulates the expression of p63 and its target genes GJB6 and DLX5 in human palatal keratinocytes (Mammadova et al, 2014).…”

Section: Ra Inhibits the Expression Of Sox9 Andmentioning

confidence: 99%

See 1 more Smart Citation

Retinoic acid signalling in the development of the epidermis, the limbs and the secondary palate

Mammadova

Zhou²,

Carels³

et al. 2016

Differentiation

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Effects of retinoic acid on proliferation and gene expression of cleft and non-cleft palatal keratinocytes

Abstract: Overall, RA similarly inhibits proliferation of palatal KCs from cleft and non-cleft subjects and reduces the expression of specific genes.

Cited by 5 publications

References 46 publications

p63 establishes epithelial enhancers at critical craniofacial development genes

p63 establishes epithelial enhancers at critical craniofacial development genes

Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors

Retinoic acid signalling in the development of the epidermis, the limbs and the secondary palate

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