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Cleft Palate: Players, Pathways, and Pursuits

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Cleft Palate: Players, Pathways, and Pursuits Cleft palate: players, pathways, and pursuits Jeffrey C. Murray, Brian C. Schutte J Clin Invest. 2004;113(12):1676-1678. https://doi.org/10.1172/JCI22154. Commentary Cleft lip and palate is a common human birth defect, and its causes are being dissected through studies of human populations and through the use of animal models. Mouse models in particular have made a substantial contribution to our understanding of the gene pathways involved in palate development and the nature of signaling molecules that act in a tissue-specific manner at critical stages of embryogenesis. Related work has provided further support for investigating the role of common environmental triggers as causal covariates. Find the latest version: https://jci.me/22154/pdf Commentaries Cleft palate: players, pathways, and pursuits Jeffrey C. Murray and Brian C. Schutte Department of Pediatrics and Craniofacial Anomalies Research Center, University of Iowa, Iowa City, Iowa, USA. Cleft lip and palate is a common human birth defect, and its causes are being mon isolated cleft is a complex trait caused dissected through studies of human populations and through the use of ani- by multiple gene mutations and/or environ- mal models. Mouse models in particular have made a substantial contribu- mental insults. Very recently it was demon- tion to our understanding of the gene pathways involved in palate devel- strated that a common haplotype associated opment and the nature of signaling molecules that act in a tissue-specific with IRF6 contains a mutation that provides manner at critical stages of embryogenesis (see the related article beginning an attributable risk of approximately 12% on page 1692). Related work has provided further support for investigating to all common forms of cleft lip and palate the role of common environmental triggers as causal covariates. (7). In a second report, nonsense mutations and deletions in the FGFR1 gene were identi- Human birth defects arise from many etiol- that lead to palate growth and development fied in cases of Kallmann syndrome (8), an ogies, including single-gene disorders, chro- (2). They demonstrate a signaling process in autosomal dominant disorder typically char- mosome aberrations, exposure to teratogens, which Fgf10 is expressed in the mesenchyme, acterized by infertility and anosmia. Howev- and sporadic conditions of unknown cause. then activates its receptor, FGF receptor 2b er, approximately 5% of Kallmann syndrome Birth defect syndromes include multiple (Fgfr2b), which is located in the epithelium. cases have clefts of the lip and/or palate and, structural abnormalities and/or cognitive Finally, Fgfr2b mediates expression of sonic as with VWS, some individuals may present delays. However, most human birth defects hedgehog (Shh) in the epithelium. with clefts as the only component of the affect a single organ system, and those Additional genetic factors involved in pal- phenotype. Other genes that play a role in disrupting facial structures are found in ate development have been described using human palate development were reviewed approximately 1% (or 1 million) of infants mouse transgenic models; in particular, mice recently (P63, PVRL1, TGFA, and TBX22; ref born worldwide each year. The most com- lacking the muscle segment–specific homeo- 1) or were reported (SATB2) (9). mon of these birth defects is cleft lip and/or box Msx1 (3) or the signaling molecule Tgfb3 One remarkable feature of the genes IRF6, palate, a complex trait caused by multiple (4) exhibit cleft palate. While many other MSX1, and FGFR1 is that mutations in any of genetic and environmental factors (1). gene knockouts also result in palate or other the three are associated with dental anoma- craniofacial defects, in most cases the gene lies and “mixed clefting.” Mixed clefting Genes that play a role in palate deletions and/or insertions cause multiple refers to disorders in which cases of isolated development structural or functional defects. Consequent- cleft palate and cleft lip (with or without cleft As shown in Figure 1, the secondary palate ly, evaluation of the role of a particular gene palate) occur in the same pedigree. Clefts of develops as an outgrowth of the maxillary in palate formation has not been possible. the lip or clefts of the lip with the palate arise prominences at about embryonic day (E) The function of Msx1 and Tgfb3 in palate in the primary palate, whereas clefts of the 11.5 in the mouse. The palate shelves ini- development was extended to isolated forms palate alone occur in the secondary palate. tially grow vertically down the side of the of clefting in humans. Point mutations and/ Mixed clefting disorders suggest that iden- tongue (E12.5) and then elevate above the or statistical analyses have indicated a role tical mechanisms cause these two forms, tongue as it drops in the oral cavity (E13.5). for these factors in cases of cleft lip and/or which previously had been separated based With continued growth, the shelves appose palate in which the only other feature was on embryologic and genetic evidence (1). The in the midline (E14.5) and fuse (E15.5). dental abnormalities (1, 5). In parallel with presence of dental anomalies in some indi- Growth of the palate shelves depends on the advances made from the study of animal viduals who have mutations in each of these the survival and continued proliferation models, complementary progress has been three genes suggests that these same path- of mesenchymal cells that originate from made to identify additional genes that play a ways are common to tooth development. neural crest and mesodermal cells of the direct role in human palate development. first pharyngeal arch. In this issue of the JCI, Two recent gene discovery reports are par- Pathways in palate development using transgenic animal models Rice and ticularly relevant to human palate develop- In addition to demonstrating the essen- coworkers provide details of the interactions ment. In the first, mutations were identified tial role of the Fgf10/Fgfr2/Shh signaling between the epithelium and mesenchyme in the gene that encodes the transcription fac- pathway in palate development, Rice and tor interferon regulatory factor 6 (IRF6), result- coworkers (2) integrate this model into the ing in the autosomal dominant disorder Msx1 pathway. Zhang et al. (10) previously Nonstandard abbreviations used: embryonic day (E); Van der Woude syndrome (VWS) (6). VWS demonstrated that Msx1, bone morpho- FGF receptor 2b (Fgfr2b); interferon regulatory factor 6 (IRF6); sonic hedgehog (Shh); Van der Woude syndrome is an especially important model for isolated genetic protein 4 (Bmp4), Shh, and Bmp2 (VWS). cleft lip and palate. In the clinic, the only dif- constitute a pathway that is essential for Conflict of interest: The authors serve as unpaid con- ference between individuals with VWS and palate development in mice. Figure 1 shows sultants to GeneDx Inc., which offers molecular testing those with isolated cleft lip and palate is the an expansion of the models presented in for the IRF6 gene. presence of pits in the lower lip of most VWS those papers and incorporates known and Citation for this article: J. Clin. Invest. 113:1676–1678 (2004). cases. In addition, VWS is caused by muta- speculative interactions between these and doi:10.1172/JCI200422154. tions in a single gene, whereas the more com- other signaling pathways in lip and palate 1676 The Journal of Clinical Investigation http://www.jci.org Volume 113 Number 12 June 2004 commentaries Figure 1 Signaling molecules essential for palate development. (A) Trans- verse section of embryonic palate. (B) Schematic of sections of normal palate shelf (ps; blue) development at the indicated days after conception. Palate shelves emanate from maxil- lary prominences (E11.5), grow, and extend vertically past the tongue (E12.5). The tongue (T; pink) drops, allowing the palate shelves to elevate (E13.5), appose (E14.5), and fuse (E15.5). (C and D) Cell-specific expression of signaling mole- cules during palate growth (C) and fusion (D). Genes involved in palate growth may also be involved in fusion. The γ-ami- nobutyric acid receptor subunit β3 (Gabrb3) is also involved in palate elevation (not shown). Molecules are expressed in the epithelium (yellow) or mesenchyme (blue). Molecules shown to be essential for palate development are indicated for mouse (oval), human (underlined), and both mouse and human (rectangle). Arrows indicate known (black) or predict- ed (gray) gene-gene (straight) and gene-environment (wavy) interactions. Ahr, aryl-hydrocarbon receptor; Alk5, activin receptor–like kinase 5; Bmp4, bone morphogenic protein 4; Bzd’s, benzodiazepines; Msx1, msh-like 1 homeo box; Ptc, patched homolog 1; Pvrl1, poliovirus receptor–related 1; SATB2, SATB family member 2; TBX22, T-box 22; Tgfb3, transforming growth factor β3. development. First, we show other proteins classes of environmental triggers have been the great genetic public health successes in pathways, including Shh. These path- studied. One of these is teratogens. Mater- of the twentieth century (19). Cholesterol ways drive the epithelium and mesenchyme nal smoking, for example, has been recog- is an essential component of Shh signal- interactions that support cell proliferation nized as an important covariate in clefting ing. The central role for Shh presented by and palate growth (Figure 1C). In addi- (16). Other teratogens that increase the risk Rice and colleagues in this issue of the JCI tion, we posit that FGFR1 (11), SATB2 (9), of cleft lip and palate through maternal provides further support for the idea that and TBX22 (12) are also involved in palate ingestion include pharmaceuticals, such normal variations in cholesterol metabo- growth in humans and/or mice, although as the anticonvulsant phenytoin and ben- lism and/or disruptions in cholesterol their exact placement in a known pathway zodiazepines, or pesticides, such as dioxin levels through pharmacological interven- remains to be determined.
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