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Development of the upper lip: Morphogenetic and molecular mechanisms
Article first published online: 16 NOV 2005
DOI: 10.1002/dvdy.20646
Copyright © 2005 Wiley-Liss, Inc.
Issue

Developmental Dynamics
Special Issue: Craniofacial Development Special Issue
Volume 235, Issue 5, pages 1152–1166, May 2006
Additional Information
How to Cite
Jiang, R., Bush, J. O. and Lidral, A. C. (2006), Development of the upper lip: Morphogenetic and molecular mechanisms. Dev. Dyn., 235: 1152–1166. doi: 10.1002/dvdy.20646
Publication History
- Issue published online: 19 APR 2006
- Article first published online: 16 NOV 2005
- Manuscript Accepted: 13 OCT 2005
Funded by
- NIH. Grant Numbers: DE013681, DE015207, DE016215, DE07202, DE015291, DE014667
REFERENCES
- , , , , . 2002. Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development 129: 4613–4625.
- , . 1999. Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death. Curr Biol 9: 1304–1314.
- , , . 2002. Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sci U S A 99: 10476–10481.
- . 1999. Folinic acid reduces cleft lip [CL(P)] in A/WySn mice. Teratology 60: 344–347.Direct Link:
- , , , . 2002. Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 251: 320–332.
- , , . 2002. Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion. Development 129: 4647–4660.
- , . 2001. Expression of members of the Fgf family and their receptors during midfacial development. Mech Dev 100: 313–316.
- , . 1997. Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 124: 391–398.
- , , , , , , . 2003. Ectodermal Wnt3/beta -catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev 17: 394–409.
- , , . 2004. Molecular mechanisms of neural crest induction. Birth Defects Res C Embryo Today 72: 109–123.Direct Link:
- , , , , . 2001. Severe nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice. Development 128: 3975–3986.
- . 2005. beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol 15: R64–R67.
- , , . 2004. The cleft lip and palate defects in Dancer mutant mice result from gain of function of the Tbx10 gene. Proc Natl Acad Sci U S A 101: 7022–7027.
- , . 1997. Wnt signaling: a common theme in animal development. Genes Dev 11: 3286–3305.
- , . 1992. The fate of medial edge epithelial cells during palatal shelf fusion in vitro: an analysis by DiI labeling and confocal microscopy. Development 114: 379–388.
- , , , , . 2005. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the Mammalian urogenital system. Dev Cell 9: 283–292.
- , . 2002. Neural crest: facing the facts of head development. Trends Genet 18: 381–384.
- , . 1973. Palatogenesis in hamster. II. Ultrastructural observations on the closure of palate. J Morphol 139: 329–350.Direct Link:
- , . 2005. Roles of FGF signaling in skeletal development and human genetic diseases. Front Biosci 10: 1961–1976.
- , , , , , , . 1996. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383: 407–413.
- , , , , , . 1995. Murine Wnt-11 and Wnt-12 have temporally and spatially restricted expression patterns during embryonic development. Mech Dev 51: 341–350.
- . 2004. The complex genetics of cleft lip and palate. Eur J Orthod 26: 7–16.
- , , , , . 1999. Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Dev Dyn 216: 72–88.Direct Link:
- , , . 1992. The developmental fate of the cephalic mesoderm in quail-chick chimeras. Development 114: 1–15.
- , , . 1993. The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 117: 409–429.
- . 2004. Taking it to the max: the genetic and developmental mechanisms coordinating midfacial morphogenesis and dysmorphology. Clin Genet 65: 163–176.Direct Link:
- , . 2004. Death is the major fate of medial edge epithelial cells and the cause of basal lamina degradation during palatogenesis. Development 131: 15–24.
- , , , . 2002. Programmed cell death is required for palate shelf fusion and is regulated by retinoic acid. Dev Biol 245: 145–156.
- , , , . 2005. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev 16: 233–247.
- , . 1999. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126: 4557–4568.
- , . 1968. Ultrastructure of mouse and rat palatal processes prior to and during secondary palate formation. Arch Oral Biol 13: 601–608.
- , . 1966. A new gene affecting the morphogenesis of the vestibular part of the inner ear in the mouse. J Embryol Exp Morphol 16: 543–558.
- , . 1992. Recent advances in primary palate and midface morphogenesis research. Crit Rev Oral Biol Med 4: 111–130.
- , , , , , , , , , , , , , , . 2004. A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet 36: 1111–1116.
- , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . 2003. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33: 463–465.
- , . 1999. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol 11: 233–240.
- , , , , , , . 1993. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75: 1417–1430.
- , , . 2005. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16: 139–149.
- . 1988. Palate development. Development 103(Suppl): 41–60.
- , , , . 2002. Molecular basis of environmentally induced birth defects. Annu Rev Pharmacol Toxicol 42: 181–208.
- , . 2002. FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region. Dev Biol 247: 237–250.
- , . 1989. Medial edge epithelium transforms to mesenchyme after embryonic palatal shelves fuse. Dev Biol 131: 455–474.
- , , . 1989. Reduced epithelial surface activity is related to a higher incidence of facial clefting in A/WySn mice. J Craniofac Genet Dev Biol 9: 271–283.
- , , . 1994. Expression patterns of the bone morphogenetic protein genes Bmp-4 and Bmp-2 in the developing chick face suggest a role in outgrowth of the primordia. Dev Dyn 201: 168–178.
- , , , . 1998. Signalling interactions during facial development. Mech Dev 75: 3–28.
- , , . 2003. Craniofacial development: the tissue and molecular interactions that control development of the head. Adv Anat Embryol Cell Biol 169: III–VI, 1–138.
- , , , , , , . 2002. An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development 129: 4591–4603.
- . 1970. The genetics of cleft lip and cleft palate. Am J Hum Genet 22: 336–352.
- , . 1970. Relation of face shape to susceptibility to congenital cleft lip: a preliminary report. J Med Genet 7: 112–117.
- , , , , , , , , , , , , , , , , , , , , , , , , , , , . 2005. Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet (in press [DOI: 10.1136/jmg.2005.03185](.
- , . 1977a. Fusion of nasal swellings in the mouse embryo: surface coat and initial contact. Am J Anat 150: 461–475.Direct Link:
- , . 1977b. Fusion of nasal swellings in the mouse embryo: regression of the nasal fin. Am J Anat 150: 477–499.Direct Link:
- , , . 1990. Expression of multiple novel Wnt-1/int-1-related genes during fetal and adult mouse development. Genes Dev 4: 2319–2332.
- . 1965. Cell death in normal development. Arch Biol (Liege) 76: 419–437.
- , . 2003. Bmp4 gene is expressed at the putative site of fusion in the midfacial region. Differentiation 71: 228–236.Direct Link:
- , , . 2000. The Twirler mouse, a model for the study of cleft lip and palate. Arch Oral Biol 45: 87–94.
- , , . 2001. Syndromes of the head and neck. New York: Oxford University Press.
- , , . 2004. Significance of the cranial neural crest. Dev Dyn 229: 5–13.Direct Link:
- , . 1992. Epithelial-mesenchymal transformation during palatal fusion: carboxyfluorescein traces cells at light and electron microscopic levels. Development 116: 1087–1099.
- , , , , , , , , , , , , , , , , , , , , . 1996. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85: 841–851.
- . 1995. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154: 8–20.
- . 2005. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233: 706–720.Direct Link:
- , , . 2005. New insights into craniofacial morphogenesis. Development 132: 851–861.
- . 1985. The early development of morphology and patterns of the face in the human embryo. Adv Anat Embryol Cell Biol 98: 1–79.
- , . 1974. Epithelial morphology during closure of the secondary palate in the rat. Arch Oral Biol 19: 969–980.
- , . 2002. Apoptotic epithelial cell death: a prerequisite for palatal fusion. An in vivo study in rabbits. J Craniomaxillofac Surg 30: 329–336.
- , . 1999. The role of sonic hedgehog in normal and abnormal craniofacial morphogenesis. Development 126: 4873–4884.
- , . 2004. Induction of the neural crest and the opportunities of life on the edge. Dev Biol 275: 1–11.
- , . 2001. New aspects of Wnt signaling pathways in higher vertebrates. Curr Opin Genet Dev 11: 547–553.
- , . 2001. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15: 3059–3087.
- , , , , . 2004. The presence of FGF2 signaling determines whether beta-catenin exerts effects on proliferation or neuronal differentiation of neural stem cells. Dev Biol 268: 220–231.
- , . 2004. Evolution of the Fgf and Fgfr gene families. Trends Genet 20: 563–569.
- , , , , . 2004. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev 18: 937–951.
- , . 2000. Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 92: 19–29.
- , , , , , , , , , , , , , , , , . 2003. Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet 40: 399–407.
- , . 1995. Prenatal craniofacial development: new insights on normal and abnormal mechanisms. Crit Rev Oral Biol Med 6: 368–422.
- , . 1985. Normal and abnormal development of the lip and palate. Clin Plast Surg 12: 521–532.
- , . 1995. The major locus for multifactorial nonsyndromic cleft lip maps to mouse chromosome 11. Mamm Genome 6: 63–69.
- , , . 1996. The clf1 gene maps to a 2- to 3-cM region of distal mouse chromosome 11. Mamm Genome 7: 789.
- , , . 2001. Unravelling the complex genetics of cleft lip in the mouse model. Mamm Genome 12: 426–435.
- , , . 2004. A digenic cause of cleft lip in A-strain mice and definition of candidate genes for the two loci. Birth Defects Res A Clin Mol Teratol 70: 509–518.Direct Link:
- , , , , , , . 2005. Investigations of the genomic region that contains the clf1 mutation, a causal gene in multifactorial cleft lip and palate in mice. Birth Defects Res A Clin Mol Teratol 73: 103–113.Direct Link:
- , , , , , . 2001. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell 104: 891–900.
- , , , , , , , , , , . 2005. Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. J Med Genet 42: 666–672.
- , , . 2004. Comparative analysis of neural crest cell death, migration, and function during vertebrate embryogenesis. Dev Dyn 229: 14–29.Direct Link:
- . 1970. Cleft lip induced in the rat. Cleft Palate J 7: 169–186.
- , . 2004. Genetic approaches to identify disease genes for birth defects with cleft lip/palate as a model. Birth Defects Res A Clin Mol Teratol 70: 893–901.Direct Link:
- , , , , , , , , , , , , . 1998. Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. Am J Hum Genet 63: 557–568.
- , , , , , , , , , . 2005a. Threshold-specific requirements for Bmp4 in mandibular development. Dev Biol 283: 282–293.
- , , , , , , . 2005b. Distinct functions for Bmp signaling in lip and palate fusion in mice. Development 132: 1453–1461.
- , , , , , , , . 1994. Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120: 2723–2748.
- . 1958. Twirler: a mutant affecting the inner ear of the house mouse. J Embryol Exp Morphol 6: 105–116.
- , . 2004. Current concepts in the embryology and genetics of cleft lip and cleft palate. Clin Plast Surg 31: 125–140.
- , , , , , . 2000. Medial edge epithelial cell fate during palatal fusion. Dev Biol 220: 343–357.
- , , . 1998. Fate map of the developing chick face: analysis of expansion of facial primordia and establishment of the primary palate. Dev Dyn 212: 102–118.Direct Link:
- , , . 2003. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 53: 1–114.
- , , , , . 1999. Vertebrate aristaless-related genes. Int J Dev Biol 43: 651–663.
- , , , , , , . 2004. Tcf3: a transcriptional regulator of axis induction in the early embryo. Development 131: 263–274.
- , , , , , , . 1999. Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nat Genet 22: 69–73.
- , . 1981. Active role of embryonic facial epithelium: new evidence of cellular events in morphogenesis. J Embryol Exp Morphol 63: 53–66.
- , , . 1982. Developmental alterations associated with spontaneous cleft lip and palate in CL/Fr mice. Am J Anat 164: 29–44.Direct Link:
- , , , , . 1994. Cytochemical identification of programmed cell death in the fusing fetal mouse palate by specific labelling of DNA fragmentation. Anat Embryol (Berl) 190: 21–28.
- , , . 2002. Pathways and consequences: Hedgehog signaling in human disease. Trends Cell Biol 12: 562–569.
- . 2002. Gene/environment causes of cleft lip and/or palate. Clin Genet 61: 248–256.Direct Link:
- , . 2004. Cleft palate: players, pathways, and pursuits. J Clin Invest 113: 1676–1678.
- , , . 2004. Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol 49: 675–689.
- , , , . 1997. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90: 247–255.
- , , , , , , , . 2004. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet 74: 558–563.
- , , , , , , . 2000. Interaction between Wnt and TGF-beta signalling pathways during formation of Spemann's organizer. Nature 403: 781–785.
- . 2002. Interplay between the molecular signals that control vertebrate development. Int J Dev Biol 46: 877–881.
- . 1978. The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Dev Biol 67: 296–312.
- . 1983. The embryonic origins of avian cephalic and cervical muscles and associated connective tissues. Am J Anat 168: 257–276.Direct Link:
- . 1988. Interactions and fates of avian craniofacial mesenchyme. Development 103(Suppl): 121–140.
- , , , . 2004. Signal transduction of bone morphogenetic protein receptors. Cell Signal 16: 291–299.
- , , , , . 1998. AP-2-null cells disrupt morphogenesis of the eye, face, and limbs in chimeric mice. Proc Natl Acad Sci U S A 95: 13714–13719.
- , . 1986. Relative contributions of the facial processes to facial development: a microsurgical assay. J Craniofac Genet Dev Biol Suppl 2: 41–44.
- , , , , , , . 1993. Differential expression of the HMG box factors TCF-1 and LEF-1 during murine embryogenesis. Development 118: 439–448.
- . 1972. Guide to the staging of human embryos. Anat Anz 130: 556–559.
- , , , . 1993. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Development 119: 247–261.
- , . 2002. Folate and the face: evaluating the evidence for the influence of folate genes on craniofacial development. Cleft Palate Craniofac J 39: 327–331.
- , , , , . 1999. Physical and genetic interactions between Alx4 and Cart1. Development 126: 359–369.
- , , , , , , , . 2004. Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest 113: 1692–1700.
- , . 1989. Epithelia are interchangeable between facial primordia of chick embryos and morphogenesis is controlled by the mesenchyme. Dev Biol 136: 201–210.
- , . 2003. How a Hedgehog might see holoprosencephaly. Hum Mol Genet 12 Spec No 1: R15–25.
- , . 1994. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet 6: 348–356.
- 1966. Death in embryonic systems. Science 154: 604–612.
- , . 1999. The many faces and factors of orofacial clefts. Hum Mol Genet 8: 1853–1859.
- , , , . 2003. Development of the upper lip. Arch Facial Plast Surg 5: 16–25.
- , . 1969. Electron microscopic and histochemical examination of oral epithelial-mesenchymal interaction (programmed cell death). J Dent Res 48: 652–660.
- , . 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113: 685–700.
- , , , , , , , , , , . 2005. Wnt/b-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Dev Biol 283: 226–239.
- , , , . 1991. Molecular and morphologic changes during the epithelial-mesenchymal transformation of palatal shelf medial edge epithelium in vitro. Int J Dev Biol 35: 463–472.
- , , , . 1992. Medial edge epithelium fate traced by cell lineage analysis during epithelial-mesenchymal transformation in vivo. Dev Biol 154: 318–330.
- , . 1968. Fine structure of midline epithelium in the developing palate of the mouse. Anat Rec 161: 293–310.Direct Link:
- , . 1975. A comparison of secondary palate development with different in vitro techniques. Anat Rec 181: 711–723.Direct Link:
- . 1997. The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites. Development 124: 2691–2700.
- . 1999. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21: 70–71.
- , , , , , , , . 2003. Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb. Genes Dev. 17: 1963–1968.
- . 2002. Formation of the primary palate. In: WyszynskiDF, editor. Cleft lip and palate: from origin to treatment. New York: Oxford University Press. p 5–13.
- , , , , , , , . 2000. Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage. Dev Biol 217: 323–332.
- , , , . 1998. TGFbeta3 promotes transformation of chicken palate medial edge epithelium to mesenchyme in vitro. Development 125: 95–105.
- , , . 2000. Epithelial-mesenchymal transformation is the mechanism for fusion of the craniofacial primordia involved in morphogenesis of the chicken lip. Dev Biol 228: 337–349.
- , , . 2003. Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development. PLoS Biol 1: E52.
- , , . 1995. Apoptosis and heterophagy of medial edge epithelial cells of the secondary palatine shelves during fusion. Arch Histol Cytol 58: 191–203.
- , , , . 1999. Regulation of ribosomal S6 protein kinase-p90(rsk), glycogen synthase kinase 3, and beta-catenin in early Xenopus development. Mol Cell Biol 19: 1427–1437.
- . 1968. Pathogenesis of cleft lip and its relation to embryonic face shape in A-J and C57BL mice. Teratology 1: 33–49.Direct Link:
- , . 1983. Ultrastructure of initial nasal process cell fusion in spontaneous and 6-aminonicotinamide-induced mouse embryo cleft lip. Teratology 28: 91–101.Direct Link:
- , , , . 2003. Fgfr1 regulates patterning of the pharyngeal region. Genes Dev 17: 141–153.
- , , , , . 1999. Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev 13: 3136–3148.
- , , , , , , , . 2004. Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A 101: 8652–8657.
- , , , . 2000. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 24: 342–343.
- . 1987. Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Cleft Palate J 24: 216–225.
- , , , , , . 2005. Fate-mapping of the epithelial seam during palatal fusion rules out epithelial-mesenchymal transformation. Dev Biol 285: 490–495.
- , . 2005. BMP signaling in skeletal development. Biochem Biophys Res Commun 328: 651–657.
- , . 1996. Murine Wnt10a and Wnt10b: cloning and expression in developing limbs, face and skin of embryos and in adults. Oncogene 13: 1537–1544.
- , , . 1995. Deficient and delayed primary palatal fusion and mesenchymal bridge formation in cleft lip-liable strains of mice. J Craniofac Genet Dev Biol 15: 99–116.
- . 1987. Epithelial-mesenchymal interactions in the development of chick facial primordia and the target of retinoid action. Development 99: 341–351.
- , , , , , , , . 2004. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 74: 1209–1215.
- , . 2001. Genetics of craniofacial development and malformation. Nat Rev Genet 2: 458–468.
- , . 1998. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14: 59–88.
- , , , , , , , . 1988. Novel regulators of bone formation: molecular clones and activities. Science 242: 1528–1534.
- , , , , . 2004. Molecular shaping of the beak. Science 305: 1465–1466.
- . 2002. Cleft lip and palate. New York: Oxford University Press.
- , . 1978. Facial development in normal and mutant chick embryos. I. Scanning electron microscopy of primary palate formation. J Exp Zool 206: 307–321.Direct Link:
- , , , , . 2000. Development of the lip and palate in staged human embryos and early fetuses. Yonsei Med J 41: 477–484.
- , , , . 2000. Genetic and teratogenic approaches to craniofacial development. Crit Rev Oral Biol Med 11: 304–317.
- , , , , , . 1997. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells. Proc Natl Acad Sci U S A 94: 3789–3794.
- , , , , , . 2002. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 129: 4135–4146.

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