<i>MCS9.7</i> enhancer activity is highly, but not completely, associated with expression of Irf6 and p63

Fakhouri, Walid D.; Rhea, Lindsey; Du, Tianli; Sweezer, Eileen; Morrison, Harris; FitzPatrick, David R.; Yang, Baoli; Dunnwald, Martine; Schutte, Brian C.

doi:10.1002/dvdy.22786

Cited by 35 publications

(13 citation statements)

References 25 publications

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“…Recent studies have revealed that downregulation of ΔNp63 in MEE occurs during normal palatal fusion (Fakhouri et al, 2012; Hu et al, 2014; Thomason et al, 2010), and increased expression of ΔNp63 in MEE is detected in Tgfbr2 fl/fl ;K14-Cre embryos in which MEE persistence occurs (Iwata et al, 2013). In addition, the expression of ΔNp63 is known to be regulated by BMP signaling (Bakkers et al, 2002; Medawar et al, 2008; Tribulo et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice

Noda¹,

Mishina²,

Komatsu³

2016

Developmental Biology

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Cleft palate is among the most common human birth defects. Submucous cleft palate (SMCP) is a subgroup of cleft palate, which may be as common as overt cleft palate. Despite the high frequency of SMCP in humans, only recently have several animal models of SMCP begun to provide insight into the mechanisms by which SMCP develops. In this study, we show that enhanced BMP signaling through constitutively active ACVR1 in palatal epithelium causes submucous cleft palate in mice. In these mutant mice, the fusion of both palatal mesenchyme in hard palate, and muscles in soft palate were hampered by epithelial tissue. During palatal fusion, enhanced SMAD-dependent BMP signaling impaired cell death and altered cell proliferation rate in medial edge epithelium (MEE), and resulted in MEE persistence. At the molecular level, downregulation of ΔNp63, which is crucial for normal palatal fusion, in MEE cells was impaired, leading to a reduction in caspase-3 activation. Our study provides a new insight into the etiology of SMCP caused by augmented BMP signaling.

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Section: Resultsmentioning

confidence: 99%

Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice

Noda¹,

Mishina²,

Komatsu³

2016

Developmental Biology

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“…However, in a recent study, a mouse Irf6 enhancer (MCS9.7) was fused to the B-galactosidase gene and showed strong expression in the hindbrain and some expression in the anterior pole of the forebrain early in development [Fakhouri et al, 2012]. Additional work is needed to connect the observed phenotypic changes to altered gene expression and to pinpoint the timing and sequencing of events leading to abnormal brain morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of interferon regulatory factor 6 alters brain morphology in the mouse

Aerts

DeVolder

Weinberg

et al. 2013

American J of Med Genetics Pt A

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Orofacial clefts are among the commonest birth defects. Among many genetic contributors to orofacial clefting, Interferon Regulatory Factor 6 (IRF6) is unique since mutations in this gene cause Van der Woude (VWS), the most common clefting syndrome. Furthermore, variants in IRF6 contribute to increased risk for non-syndromic cleft lip and/or palate (NSCL/P). Our previous work shows that individuals with either VWS or NSCL/P may have cerebral anomalies (larger anterior, smaller posterior regions), and a smaller cerebellum. The objective of this study was to test the hypothesis that disrupting Irf6 in the mouse will result in quantitative brain changes similar to those reported for humans with VWS and NSCL/P. Male mice heterozygous for Irf6 (Irf6gt1/+; n = 9) and wild type (Irf6+/+; n = 6) mice at comparable age underwent a 4.7T MRI scan to obtain quantitative measures of cortical and subcortical brain structures. There was no difference in total brain volume between groups. However, the frontal cortex was enlarged in the Irf6gt1/+ mice compared to that of wild types (p = 0.028) while the posterior cortex did not differ. In addition, the volume of the cerebellum of Irf6gt1/+ mice was decreased (p = 0.004). Mice that were heterozygous for Irf6 showed a similar pattern of brain anomalies previously reported in humans with VWS and NSCL/P. These structural differences were present in the absence of overt oral clefts. These results support a role for IRF6 in brain morphometry and provide evidence for a potential genetic link to abnormal brain development in orofacial clefting.

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“…Remarkably, whereas initial differentiation of the periderm cells requires Irf6 function, recent studies suggest that Irf6 is also required to mediate Tgfb3-induced palatal fusion. This second important function of Irf6 in palate development is brought about by Tgfb3 activation of its expression in the basal layer of the MEE cells just prior to palatal fusion (Fakhouri et al, 2012; Iwata et al, 2013). Tgfb3 −/− as well as Tgfbr2 fl/fl ;K14-Cre mutant embryos show significantly reduced Irf6 expression in MEE cells (Knight et al, 2006; Iwata et al, 2013).…”

Section: Palatal Fusion: Formation and Dissolution Of Inter-shelf mentioning

confidence: 99%

Cellular and Molecular Mechanisms of Palatogenesis

Lan

Jiang

2015

Current Topics in Developmental Biology

120

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Palatogenesis involves the initiation, growth, morphogenesis, and fusion of the primary and secondary palatal shelves from initially separate facial prominences during embryogenesis to form the intact palate separating the oral cavity from the nostrils. The palatal shelves consist mainly of cranial neural crest-derived mesenchyme cells covered under a simple embryonic epithelium. Growth and patterning of the palatal shelves are controlled by reciprocal epithelial-mesenchymal interactions regulated by multiple signaling pathways and transcription factors. During palatal shelf outgrowth, the embryonic epithelium develops a “teflon” coat consisting of a single, continuous layer of periderm cells that prevents the facial prominences and palatal shelves from forming aberrant inter-epithelial adhesions. Palatal fusion involves not only spatiotemporally-regulated disruption of the periderm but also dynamic cellular and molecular processes that result in adhesion and intercalation of the palatal medial edge epithelia to form an inter-shelf epithelial seam, and subsequent dissolution of the epithelial seam to form the intact roof of the oral cavity. The complexity of regulation of these morphogenetic processes is reflected by the common occurrence of cleft palate in humans. This review will summarize major recent advances and discuss major remaining gaps in the understanding of cellular and molecular mechanisms controlling palatogenesis.

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MCS9.7 enhancer activity is highly, but not completely, associated with expression of Irf6 and p63

Cited by 35 publications

References 25 publications

Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice

Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice

Haploinsufficiency of interferon regulatory factor 6 alters brain morphology in the mouse

Cellular and Molecular Mechanisms of Palatogenesis

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