Biological Mechanisms in Palatogenesis and Cleft Palate

Meng, Liuyan; Bian, Zhuan; Torensma, Ruurd; Hoff, Johannes W. Von den

doi:10.1177/0022034508327868

Cited by 152 publications

(176 citation statements)

References 156 publications

(133 reference statements)

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…This process is mediated by transforming growth factor beta (TGFβ) signaling (reviewed in ref. 45). Our data support the concept that the CS Fgfr2 mutation does not affect the TGFβ-mediated fusion process.…”

Section: Discussionsupporting

confidence: 86%

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

Snyder‐Warwick¹,

Perlyn

Pan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cleft palate is a common birth defect in humans and is a common phenotype associated with syndromic mutations in fibroblast growth factor receptor 2 (Fgfr2). Cleft palate occurred in nearly all mice homozygous for the Crouzon syndrome mutation C342Y in the mesenchymal splice form of Fgfr2. Mutant embryos showed delayed palate elevation, stage-specific biphasic changes in palate mesenchymal proliferation, and reduced levels of mesenchymal glycosaminoglycans (GAGs). Reduced levels of feedback regulators of FGF signaling suggest that this gain-of-function mutation in FGFR2 ultimately resembles loss of FGF function in palate mesenchyme. Knowledge of how mesenchymal FGF signaling regulates palatal shelf development may ultimately lead to pharmacological approaches to reduce cleft palate incidence in genetically predisposed humans.Crouzon syndrome | fibroblast growth factor receptor 2 | cell proliferation | cell surface receptor | glycosaminoglycan C raniosynostosis syndromes, as well as syndromic and nonsyndromic cleft palate, have been associated with fibroblast growth factor receptor (FGFR) mutations. Of the four highly conserved FGFRs, FGFR2 is the most commonly mutated FGF receptor (1-4). The FGF-FGFR family is involved in multiple intracellular signaling mechanisms in embryonic development, cell growth, wound healing, and tumorigenesis. The FGFRs are receptor tyrosine kinases that signal via a ternary complex of FGFR, FGF, and glycosaminoglycans (GAGs) (5). The ternary complex formation leads to receptor dimerization, autophosphorylation, and activation of downstream signaling cascades (6).FGF-FGFR signaling is active during palatogenesis, and genetic FGF mutations may contribute to 5% of cases of nonsyndromic cleft lip and palate (7). In children with isolated cleft palate, mutations in Fgfr1, Fgfr2, Fgfr3, and Fgf8 have been identified. Additionally, single nucleotide polymorphisms in children with nonsyndromic cleft lip and palate are associated with Fgf3, Fgf7, Fgf10, Fgf18, and Fgfr1, providing confirmation of the importance of the FGF-FGFR system in palate development (7). Knockout mouse models for Fgf10 and Fgfr2b develop cleft palate (8, 9), establishing the necessity of epithelial FGF signaling in normal palatogenesis. Cleft palate in Fgf18 −/− mice (10) suggests that mesenchymal FGF signaling may also be important for palate development.Cleft palate has been associated with both gain-of-function and loss-of-function FGFR mutations (7,(11)(12)(13)(14)(15). Why gain-of-function or loss-of-function mutations result in the same palatal phenotype remains unclear, and understanding this phenomenon may provide additional insight into the pathogenesis of cleft palate. To address this question, we have focused on Crouzon syndrome (CS), a disorder resulting from a missense Fgfr2 mutation that displays an increased incidence of cleft palate in humans (14).CS occurs with an incidence of 12.5 per million births and results from genetic gain-of-function mutations in Fgfr2 (1). Craniofacial anomalies are its hallmark...

show abstract

Section: Discussionsupporting

confidence: 86%

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

Snyder‐Warwick¹,

Perlyn

Pan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Lip development precedes palate formation, and therefore improper lip fusion may secondarily affect palate fusion. Thus, a cleft lip and palate often occur concurrently (Meng et al, 2009). Pax9 is essential for lip and secondary palate formation, and is required to regulate the normal shape of palatal shelves (Peters et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

IRF6, RYK, and PAX9 Expression in Facial Tissue of Children with Cleft Palate

Smane

Pilmane

2015

Int. J. Morphol.

View full text Add to dashboard Cite

“…These processes are coordinated by secreted proteins and their signaling pathways, ExtraCellular Matrix components, and cell surface-receptors. 22 Gene targeting to knock-out specific genes in mice has generated, by the date, 84 lossof-function mutants that exhibits cleft palate. Information about these knockout models was collected from a literature review 4,21,23,50 and genes were clustered into families of cytokine/receptor, homeobox genes, and miscellaneous (Supplementary Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…21 The molecules involved in cleft palate formation in knockout models include cytokines, receptors, growth factors, ion channels, kinases, extracellular matrix proteins, homeobox genes, and transcription regulators 22,23 (Supplementary Table 1). According to the findings of this study, 46% of the cleft palate-causing genes (39 out of 84) were found to be affected by nicotine exposure.…”

Section: Several Genes Involved In Palate Development Are Affected Bymentioning

confidence: 99%

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

Öztürk

Sheldon

Sharma

et al. 2015

NICTOB

View full text Add to dashboard Cite

Introduction: Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus. Methods: To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5 mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays. Results: Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools. Conclusions: We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion. Implications: Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.

show abstract

Biological Mechanisms in Palatogenesis and Cleft Palate

Cited by 152 publications

References 156 publications

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

IRF6, RYK, and PAX9 Expression in Facial Tissue of Children with Cleft Palate

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

Contact Info

Product

Resources

About