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  • Review Article
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Cranial neural crest and the building of the vertebrate head

Nature Reviews Neuroscience volume 4, pages 806–818 (2003)Cite this article

Key Points

  • The craniofacial skeleton encases the brain and sensory organs, and is important for the functioning of the digestive and respiratory tracts. It is derived largely from the neural crest, a migratory cell population that detaches from the embryonic neural epithelium.

  • The cranial neural crest might use a similar patterning strategy to the developing nervous system, whereby a grid-like system of positional cues is created by gradients of extracellular signals or morphogens and their intracellular molecular effectors.

  • The anteroposterior identity of each subpopulation of neural crest cells (NCCs) has a strong influence on the development of the craniofacial skeleton. Along this axis, positional identity is determined by the nested expression of Hox genes. Dlx genes seem to provide positional identity along the dorsoventral axis of the pharyngeal arches.

  • There has been a long-standing debate about cranial NCC prepatterning versus plasticity. Skeletogenic NCCs could be irreversibly committed before they migrate, or they might maintain a broad plasticity until they reach their final destination. The accumulating evidence indicates that the reality lies somewhere in-between these two models.

  • The processes that underlie the morphogenesis of the craniofacial skeleton seem to be regulated by epithelial–mesenchymal bidirectional cross-talk. Signals from the epithelium trigger a local response in the underlying mesenchyme, which in turn initiates a differentiation programme and signals back to the epithelium.

  • A gradient of endothelin-1 signalling, which diffuses from the pharyngeal arch epithelium and mesoderm, provides a general instruction for bone differentiation, and its concentration range is translated into morphogenetic information that indicates which bone to make.

  • Fibroblast growth factor 8, which is expressed in specific regions of the facial and pharyngeal ectoderm, as well as in the pharyngeal pouch endoderm, is a key factor for NCC survival. It can also induce the expression of genes that are responsible for tissue-specific NCC differentiation.

  • Other signals, including sonic hedgehog, retinoids and bone morphogenetic proteins, also have prominent roles in the specification of facial structures.

  • Very little is known about the temporal requirement for key transcription factors in the regulation of pharyngeal arch morphogenesis. Temporally regulated inactivation should allow us to define the critical time window of transcription factor function that is necessary for cranial NCC patterning.

  • It will also be important to reconstitute the signalling mechanisms that underlie epithelial–mesenchymal interactions during cellular differentiation and morphogenesis. Future research should aim to reveal how the structural organization of the NCCs at the protein level changes at each stage of development, until the cells finally settle to form a definite structure.

Abstract

Head development in vertebrates involves a complex series of molecular and morphogenetic events that generate a coordinated pattern of cartilages, bones and nerves, and result in species-specific craniofacial morphologies. A specialized cell type of neural origin, the neural crest, is central to this process, as it provides the main source of craniofacial mesenchyme. The degree of patterning information that is intrinsic to the neural crest has been recently debated, and new advances have underscored the influence of environmental signalling on the transcriptional readout that coordinates craniofacial morphogenesis in space and time.

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Figure 1: Skeletal fate of cranial neural crest cells in vertebrates.
Figure 2: Molecular integration of anteroposterior and dorsoventral patterning information.
Figure 3: Cranial neural crest cell prepatterning versus plasticity (1).
Figure 4: Cranial neural crest cell patterning versus plasticity (2).
Figure 5: Molecular pathways involved in the specification of frontonasal, maxillary, mandibular and hyoid structures.

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References

  1. Le Douarin, N. M. & Kalcheim, C. The Neural Crest (Cambridge Univ. Press, Cambridge, UK, 1999).

    Book  Google Scholar 

  2. Nichols, D. H. Neural crest formation in the head of the mouse embryo as observed using a new histological technique. J. Embryol. Exp. Morphol. 64, 105–120 (1981).

    CAS  PubMed  Google Scholar 

  3. Noden, D. M. An analysis of migratory behavior of avian cephalic neural crest cells. Dev. Biol. 42, 106–130 (1975).

    Article  CAS  PubMed  Google Scholar 

  4. Knecht, A. K. & Bronner-Fraser, M. Induction of the neural crest: a multigene process. Nature Rev. Genet. 3, 453–461 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Aybar, M. J. & Mayor, R. Early induction of neural crest cells: lessons learned from frog, fish and chick. Curr. Opin. Genet. Dev. 12, 452–458 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Gammill, L. S. & Bronner-Fraser, M. Neural crest specification: migrating into genomics. Nature Rev. Neurosci. 4, 795–805 (2003).

    Article  CAS  Google Scholar 

  7. Noden, D. M. The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Dev. Biol. 67, 296–312 (1978).

    Article  CAS  PubMed  Google Scholar 

  8. Noden, D. M. Interactions and fates of avian craniofacial mesenchyme. Development 103, S121–S140 (1988).

    Google Scholar 

  9. Le Lievre, C. L. Role of mesectodermal cells arising from the cephalic neural crest in the formation of the branchial arches and visceral skeleton. J. Embryol. Exp. Morphol. 31, 453–477 (1974).

    Google Scholar 

  10. Le Lievre, C. S. Participation of neural crest-derived cells in the genesis of the skull in birds. J. Embryol. Exp. Morphol. 47, 17–37 (1978).

    CAS  PubMed  Google Scholar 

  11. Noden, D. M. The role of the neural crest in patterning of avian cranial skeletal, connective, and muscle tissues. Dev. Biol. 96, 144–165 (1983). A seminal study investigating the skeletal fate of cranial NCCs after heterotopic transplantation. It seemed to indicate that cranial NCCs are endowed with their morphogenetic potential before migration from the neural tube, and it raised the issue of how much intrinsic patterning information is contained in the NCCs.

    Article  CAS  PubMed  Google Scholar 

  12. Couly, G. F., Coltey, P. M. & Le Douarin, N. M. The triple origin of skull in higher vertebrates: a study in quail–chick chimeras. Development 117, 409–429 (1993).

    CAS  PubMed  Google Scholar 

  13. Jiang, X., Iseki, S., Maxson, R. E., Sucov, H. M. & Morriss-Kay, G. M. Tissue origins and interactions in the mammalian skull vault. Dev. Biol. 241, 106–116 (2002). References 7, 10, 12 and 13 are key studies mapping the contributions of cranial NCCs and mesoderm to the bones of the skull vault in mice and birds.

    Article  CAS  PubMed  Google Scholar 

  14. Chambers, D. & McGonnell, I. M. Neural crest: facing the facts of head development. Trends Genet. 18, 381–384 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Richman, J. M. & Lee, S. H. About face: signals and genes controlling jaw patterning and identity in vertebrates. Bioessays 25, 554–568 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Helms, J. A. & Schneider, R. A. Cranial skeletal biology. Nature 423, 326–331 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Wolpert, L. One hundred years of positional information. Trends Genet. 12, 359–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Gurdon, J. B. & Bourillot, P. Y. Morphogen gradient interpretation. Nature 413, 797–803 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Briscoe, J. & Ericson, J. Specification of neuronal fates in the ventral neural tube. Curr. Opin. Neurobiol. 11, 43–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Dupe, V. et al. In vivo functional analysis of the Hoxa-1 3′ retinoic acid response element (3'RARE). Development 124, 399–410 (1997).

    CAS  PubMed  Google Scholar 

  22. Studer, M. et al. Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning. Development 125, 1025–1036 (1998).

    CAS  PubMed  Google Scholar 

  23. Gavalas, A. & Krumlauf, R. Retinoid signalling and hindbrain patterning. Curr. Opin. Genet. Dev. 10, 380–386 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Irving, C. & Mason, I. Signalling by FGF8 from the isthmus patterns anterior hindbrain and establishes the anterior limit of Hox gene expression. Development 127, 177–186 (2000).

    CAS  PubMed  Google Scholar 

  25. Maden, M. Role and distribution of retinoic acid during CNS development. Int. Rev. Cytol. 209, 1–77 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Kiecker, C. & Niehrs, C. A morphogen gradient of Wnt/β-catenin signalling regulates anteroposterior neural patterning in Xenopus. Development 128, 4189–4201 (2001).

    CAS  PubMed  Google Scholar 

  27. Dupe, V. & Lumsden, A. Hindbrain patterning involves graded responses to retinoic acid signalling. Development 128, 2199–2208 (2001).

    CAS  PubMed  Google Scholar 

  28. Maves, L., Jackman, W. & Kimmel, C. B. FGF3 and FGF8 mediate a rhombomere 4 signaling activity in the zebrafish hindbrain. Development 129, 3825–3837 (2002).

    CAS  PubMed  Google Scholar 

  29. Bel-Vialar, S., Itasaki, N. & Krumlauf, R. Initiating Hox gene expression: in the early chick neural tube differential sensitivity to FGF and RA signaling subdivides the HoxB genes in two distinct groups. Development 129, 5103–5115 (2002).

    CAS  PubMed  Google Scholar 

  30. Walshe, J., Maroon, H., McGonnell, I. M., Dickson, C. & Mason, I. Establishment of hindbrain segmental identity requires signaling by FGF3 and FGF8. Curr. Biol. 12, 1117–1123 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Niederreither, K., Vermot, J., Schuhbaur, B., Chambon, P. & Dolle, P. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Development 129, 3563–3574 (2002).

    CAS  PubMed  Google Scholar 

  32. Nordstrom, U., Jessell, T. M. & Edlund, T. Progressive induction of caudal neural character by graded Wnt signaling. Nature Neurosci. 5, 525–532 (2002).

    Article  PubMed  Google Scholar 

  33. Oosterveen, T. et al. Retinoids regulate the anterior expression boundaries of 5′ Hoxb genes in posterior hindbrain. EMBO J. 22, 262–269 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lumsden, A. & Krumlauf, R. Patterning the vertebrate neuraxis. Science 274, 1109–1115 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Rijli, F. M., Gavalas, A. & Chambon, P. Segmentation and specification in the branchial region of the head: the role of the Hox selector genes. Int. J. Dev. Biol. 42, 393–401 (1998).

    CAS  PubMed  Google Scholar 

  36. Schneider-Maunoury, S., Gilardi-Hebenstreit, P. & Charnay, P. How to build a vertebrate hindbrain. Lessons from genetics. C. R. Acad. Sci. III 321, 819–834 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Lumsden, A., Sprawson, N. & Graham, A. Segmental origin and migration of neural crest cells in the hindbrain region of the chick embryo. Development 113, 1281–1291 (1991).

    CAS  PubMed  Google Scholar 

  38. Serbedzija, G. N., Bronner-Fraser, M. & Fraser, S. E. Vital dye analysis of cranial neural crest cell migration in the mouse embryo. Development 116, 297–307 (1992).

    CAS  PubMed  Google Scholar 

  39. Sechrist, J., Serbedzija, G. N., Scherson, T., Fraser, S. E. & Bronner-Fraser, M. Segmental migration of the hindbrain neural crest does not arise from its segmental generation. Development 118, 691–703 (1993).

    CAS  PubMed  Google Scholar 

  40. Hunt, P. & Krumlauf, R. Deciphering the Hox code: clues to patterning branchial regions of the head. Cell 66, 1075–1078 (1991).

    Article  CAS  PubMed  Google Scholar 

  41. Trainor, P. A. & Krumlauf, R. Hox genes, neural crest cells and branchial arch patterning. Curr. Opin. Cell Biol. 13, 698–705 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Hunt, P. et al. A distinct Hox code for the branchial region of the vertebrate head. Nature 353, 861–864 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Tumpel, S., Maconochie, M., Wiedemann, L. M. & Krumlauf, R. Conservation and diversity in the cis-regulatory networks that integrate information controlling expression of Hoxa2 in hindbrain and cranial neural crest cells in vertebrates. Dev. Biol. 246, 45–56 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Trainor, P. A. & Krumlauf, R. Patterning the cranial neural crest: hindbrain segmentation and Hox gene plasticity. Nature Rev. Neurosci. 1, 116–124 (2000).

    Article  CAS  Google Scholar 

  45. Krumlauf, R. Hox genes and pattern formation in the branchial region of the vertebrate head. Trends Genet. 9, 106–112 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Prince, V. & Lumsden, A. Hoxa-2 expression in normal and transposed rhombomeres: independent regulation in the neural tube and neural crest. Development 120, 911–923 (1994). This important paper describes the analysis of chick Hoxa2 expression. Through grafting experiments, evidence is provided that the expression of Hoxa2 is intrinsic to the premigratory NCC population, thereby supporting a NCC prepatterning model.

    CAS  PubMed  Google Scholar 

  47. Rijli, F. M. et al. A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene. Cell 75, 1333–1349 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Gendron-Maguire, M., Mallo, M., Zhang, M. & Gridley, T. Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell 75, 1317–1331 (1993). References 47 and 48 describe the targeted mutation of Hoxa2 in the mouse. They revealed the pivotal role of Hoxa2 as a selector gene for patterning of the NCCs of the hyoid arch, and they represent one of the best-known examples of homeotic transformation in vertebrates.

    Article  CAS  PubMed  Google Scholar 

  49. Grammatopoulos, G. A., Bell, E., Toole, L., Lumsden, A. & Tucker, A. S. Homeotic transformation of branchial arch identity after Hoxa2 overexpression. Development 127, 5355–5365 (2000).

    CAS  PubMed  Google Scholar 

  50. Pasqualetti, M., Ori, M., Nardi, I. & Rijli, F. M. Ectopic Hoxa2 induction after neural crest migration results in homeosis of jaw elements in Xenopus. Development 127, 5367–5378 (2000).

    CAS  PubMed  Google Scholar 

  51. Hunter, M. P. & Prince, V. E. Zebrafish hox paralogue group 2 genes function redundantly as selector genes to pattern the second pharyngeal arch. Dev. Biol. 247, 367–389 (2002). References 49, 50 and 51 showed that Hoxa2 has a conserved role as a selector of hyoid identity in vertebrates, as shown by functional experiments in chick, frog and zebrafish.

    Article  CAS  PubMed  Google Scholar 

  52. Barrow, J. R. & Capecchi, M. R. Targeted disruption of the Hoxb-2 locus in mice interferes with expression of Hoxb-1 and Hoxb-4. Development 122, 3817–3828 (1996).

    CAS  PubMed  Google Scholar 

  53. Davenne, M. et al. Hoxa2 and Hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain. Neuron 22, 677–691 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Chisaka, O. & Capecchi, M. R. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature 350, 473–479 (1991).

    Article  CAS  PubMed  Google Scholar 

  55. Chisaka, O., Musci, T. S. & Capecchi, M. R. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature 355, 516–520 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Lufkin, T., Dierich, A., LeMeur, M., Mark, M. & Chambon, P. Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 66, 1105–1119 (1991).

    Article  CAS  PubMed  Google Scholar 

  57. Manley, N. R. & Capecchi, M. R. The role of Hoxa-3 in mouse thymus and thyroid development. Development 121, 1989–2003 (1995).

    CAS  PubMed  Google Scholar 

  58. Rossel, M. & Capecchi, M. R. Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 126, 5027–5040 (1999).

    CAS  PubMed  Google Scholar 

  59. Manley, N. R. & Capecchi, M. R. Hox group 3 paralogous genes act synergistically in the formation of somitic and neural crest-derived structures. Dev. Biol. 192, 274–288 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Gavalas, A. et al. Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch. Development 125, 1123–1136 (1998).

    CAS  PubMed  Google Scholar 

  61. Kuratani, S., Matsuo, I. & Aizawa, S. Developmental patterning and evolution of the mammalian viscerocranium: genetic insights into comparative morphology. Dev. Dyn. 209, 139–155 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Matsuo, I., Kuratani, S., Kimura, C., Takeda, N. & Aizawa, S. Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev. 9, 2646–2658 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Kontges, G. & Lumsden, A. Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development 122, 3229–3242 (1996). A landmark study in avian embryos, showing detailed fate-mapping data of rhombomeric NCCs and their contribution to the craniofacial structures.

    CAS  PubMed  Google Scholar 

  64. Panganiban, G. & Rubenstein, J. L. Developmental functions of the Distal-less/Dlx homeobox genes. Development 129, 4371–4386 (2002).

    CAS  PubMed  Google Scholar 

  65. Beverdam, A. et al. Jaw transformation with gain of symmetry after Dlx5/Dlx6 inactivation: mirror of the past? Genesis 34, 221–227 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Depew, M. J., Lufkin, T. & Rubenstein, J. L. Specification of jaw subdivisions by Dlx genes. Science 298, 381–385 (2002). References 65 and 66 are key papers demonstrating the dorsoventral patterning role of Dlx genes. A double Dlx-5/-6 knockout in the mouse resulted in the homeotic transformation of the lower jaw into a mirror image of the upper jaw.

    Article  CAS  PubMed  Google Scholar 

  67. Qiu, M. et al. Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. Genes Dev. 9, 2523–2538 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Qiu, M. et al. Role of the Dlx homeobox genes in proximodistal patterning of the branchial arches: mutations of Dlx-1, Dlx-2, and Dlx-1 and -2 alter morphogenesis of proximal skeletal and soft tissue structures derived from the first and second arches. Dev. Biol. 185, 165–184 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Duboule, D. & Morata, G. Colinearity and functional hierarchy among genes of the homeotic complexes. Trends Genet. 10, 358–364 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Sumiyama, K. & Ruddle, F. H. Regulation of Dlx3 gene expression in visceral arches by evolutionarily conserved enhancer elements. Proc. Natl Acad. Sci. USA 100, 4030–4034 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Price, J. A., Wright, J. T., Kula, K., Bowden, D. W. & Hart, T. C. A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families. J. Med. Genet. 35, 825–828 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Morasso, M. I., Grinberg, A., Robinson, G., Sargent, T. D. & Mahon, K. A. Placental failure in mice lacking the homeobox gene Dlx3. Proc. Natl Acad. Sci. USA 96, 162–167 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Saldivar, J. R., Krull, C. E., Krumlauf, R., Ariza-McNaughton, L. & Bronner-Fraser, M. Rhombomere of origin determines autonomous versus environmentally regulated expression of Hoxa-3 in the avian embryo. Development 122, 895–904 (1996).

    CAS  PubMed  Google Scholar 

  74. Couly, G., Grapin-Botton, A., Coltey, P., Ruhin, B. & Le Douarin, N. M. Determination of the identity of the derivatives of the cephalic neural crest: incompatibility between Hox gene expression and lower jaw development. Development 125, 3445–3459 (1998).

    CAS  PubMed  Google Scholar 

  75. Hunt, P., Clarke, J. D., Buxton, P., Ferretti, P. & Thorogood, P. Stability and plasticity of neural crest patterning and branchial arch Hox code after extensive cephalic crest rotation. Dev. Biol. 198, 82–104 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Trainor, P. A., Ariza-McNaughton, L. & Krumlauf, R. Role of the isthmus and FGFs in resolving the paradox of neural crest plasticity and prepatterning. Science 295, 1288–1291 (2002). A key study revisiting Noden's transplantation experiments and showing that duplication of the first arch skeleton could be obtained only when the FGF8-expressing isthmic organizer was included in the graft of presumptive first arch NCCs. It supports plasticity of cranial NCCs and patterning by environmental signals.

    Article  CAS  PubMed  Google Scholar 

  77. Simon, H., Hornbruch, A. & Lumsden, A. Independent assignment of antero-posterior and dorso-ventral positional values in the developing chick hindbrain. Curr. Biol. 5, 205–214 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Pasqualetti, M. & Rijli, F. M. Developmental biology: the plastic face. Nature 416, 493–494 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Couly, G., Creuzet, S., Bennaceur, S., Vincent, C. & Le Douarin, N. M. Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head. Development 129, 1061–1073 (2002). This landmark work demonstrated the role of the foregut endoderm in the control of cranial NCC development. The endoderm was shown to be a source of positional and morphogenetic information to pattern the face and jaw skeleton. It supports a NCC plasticity model.

    CAS  PubMed  Google Scholar 

  80. Creuzet, S., Couly, G., Vincent, C. & Le Douarin, N. M. Negative effect of Hox gene expression on the development of the neural crest-derived facial skeleton. Development 129, 4301–4313 (2002). References 74 and 80 revealed that Hox-expressing cranial NCCs in the first arch environment are unable to yield a jaw skeleton, thereby raising important evolutionary issues. Moreover, they indicate that Hox expression negatively regulates neural crest-mediated skeletogenesis.

    CAS  PubMed  Google Scholar 

  81. Gavalas, A., Trainor, P., Ariza-McNaughton, L. & Krumlauf, R. Synergy between Hoxa1 and Hoxb1: the relationship between arch patterning and the generation of cranial neural crest. Development 128, 3017–3027 (2001).

    CAS  PubMed  Google Scholar 

  82. Abzhanov, A., Tzahor, E., Lassar, A. B. & Tabin, V. Dissimilar regulation of cell differentiation, in mesencephalic (cranial) and sacral (trunk) neural crest cells in vitro. Development 130, 4567–4579 (2003). An interesting analysis of cultured NCCs that investigates the differential skeletogenic potential of cranial versus trunk NCCs. It is shown that the same signal (for example, FGF) can induce dissimilar cell fate decisions in the two populations in vitro . These differences correlate, at least in part, with their Hox gene expression status.

    Article  CAS  PubMed  Google Scholar 

  83. Bobola, N. et al. Mesenchymal patterning by Hoxa2 requires blocking Fgf-dependent activation of Ptx1. Development 130, 3403–3414 (2003). A paper that reports important observations about Hoxa2 -dependent molecular mechanisms in second pharyngeal arch patterning. It implicates Hoxa2 in a pathway that antagonizes epithelial FGF signalling.

    Article  CAS  PubMed  Google Scholar 

  84. Trainor, P. & Krumlauf, R. Plasticity in mouse neural crest cells reveals a new patterning role for cranial mesoderm. Nature Cell Biol. 2, 96–102 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Gurdon, J. B. A community effect in animal development. Nature 336, 772–774 (1988).

    Article  CAS  PubMed  Google Scholar 

  86. Schilling, T. F., Prince, V. & Ingham, P. W. Plasticity in zebrafish hox expression in the hindbrain and cranial neural crest. Dev. Biol. 231, 201–216 (2001). References 84 and 86 are key papers that provide evidence for NCC plasticity in mouse and zebrafish. They also show a role for the cell community effect and pharyngeal arch mesoderm in the maintenance of NCC Hox code status.

    Article  CAS  PubMed  Google Scholar 

  87. Schneider, R. A., Hu, D., Rubenstein, J. L., Maden, M. & Helms, J. A. Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development 128, 2755–2767 (2001).

    CAS  PubMed  Google Scholar 

  88. Trumpp, A., Depew, M. J., Rubenstein, J. L., Bishop, J. M. & Martin, G. R. Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev. 13, 3136–3148 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hu, D., Marcucio, R. S. & Helms, J. A. A zone of frontonasal ectoderm regulates patterning and growth in the face. Development 130, 1749–1758 (2003). In this key paper, a region of the frontonasal ectoderm that expresses Fgf8 and Shh is identified as an organizing centre, which promotes morphogenesis and outgrowth of the frontonasal NCC mesenchyme. It supports a NCC plasticity model.

    Article  CAS  PubMed  Google Scholar 

  90. David, N. B., Saint-Etienne, L., Tsang, M., Schilling, T. F. & Rosa, F. M. Requirement for endoderm and FGF3 in ventral head skeleton formation. Development 129, 4457–4468 (2002).

    CAS  PubMed  Google Scholar 

  91. Schneider, R. A. & Helms, J. A. The cellular and molecular origins of beak morphology. Science 299, 565–568 (2003). An important study showing that the ability to generate beak morphology is an intrinsic property of NCCs. By grafting presumptive cranial NCCs between duck and quail, it was shown that NCCs carry out their own species-specific morphogenetic programme. It supports a NCC prepatterning model.

    Article  CAS  PubMed  Google Scholar 

  92. Cobourne, M. T. & Sharpe, P. T. Tooth and jaw: molecular mechanisms of patterning in the first branchial arch. Arch. Oral Biol. 48, 1–14 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Mitsiadis, T. A., Cheraud, Y., Sharpe, P. & Fontaine-Perus, J. Development of teeth in chick embryos after mouse neural crest transplantations. Proc. Natl Acad. Sci. USA 100, 6541–6545 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Veitch, E., Begbie, J., Schilling, T. F., Smith, M. M. & Graham, A. Pharyngeal arch patterning in the absence of neural crest. Curr. Biol. 9, 1481–1484 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Ferguson, C. A., Tucker, A. S. & Sharpe, P. T. Temporospatial cell interactions regulating mandibular and maxillary arch patterning. Development 127, 403–412 (2000).

    CAS  PubMed  Google Scholar 

  96. Neuhauss, S. C. et al. Mutations affecting craniofacial development in zebrafish. Development 123, 357–367 (1996).

    CAS  PubMed  Google Scholar 

  97. Schilling, T. F. et al. Jaw and branchial arch mutants in zebrafish I: branchial arches. Development 123, 329–344 (1996).

    CAS  PubMed  Google Scholar 

  98. Francis-West, P., Ladher, R., Barlow, A. & Graveson, A. Signalling interactions during facial development. Mech. Dev. 75, 3–28 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Fowles, L. F. et al. Genomic screen for genes involved in mammalian craniofacial development. Genesis 35, 73–87 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Miller, C. T., Schilling, T. F., Lee, K., Parker, J. & Kimmel, C. B. sucker encodes a zebrafish Endothelin-1 required for ventral pharyngeal arch development. Development 127, 3815–3828 (2000).

    CAS  PubMed  Google Scholar 

  101. Kimmel, C. B., Miller, C. T. & Moens, C. B. Specification and morphogenesis of the zebrafish larval head skeleton. Dev. Biol. 233, 239–257 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Kimmel, C. B., Ullmann, B., Walker, M., Miller, C. T. & Crump, J. G. Endothelin 1-mediated regulation of pharyngeal bone development in zebrafish. Development 130, 1339–1351 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Miller, C. T., Yelon, D., Stainier, D. Y. & Kimmel, C. B. Two endothelin 1 effectors, hand2 and bapx1, pattern ventral pharyngeal cartilage and the jaw joint. Development 130, 1353–1365 (2003). The elegant analyses in zebrafish that are described in references 102 and 103 are interesting examples of the morphogenetic activity of locally secreted factors in branchial arch development. A functional gradient of the epithelial signalling factor endothelin-1 provides positional information to NCCs for the correct localization of specific skeletal structures.

    Article  CAS  PubMed  Google Scholar 

  104. Kurihara, Y. et al. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368, 703–710 (1994).

    Article  CAS  PubMed  Google Scholar 

  105. Clouthier, D. E. et al. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125, 813–824 (1998).

    CAS  PubMed  Google Scholar 

  106. Kempf, H., Linares, C., Corvol, P. & Gasc, J. M. Pharmacological inactivation of the endothelin type A receptor in the early chick embryo: a model of mispatterning of the branchial arch derivatives. Development 125, 4931–4941 (1998).

    CAS  PubMed  Google Scholar 

  107. Yanagisawa, H. et al. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125, 825–836 (1998).

    CAS  PubMed  Google Scholar 

  108. Ivey, K. et al. Gαq and Gα11 proteins mediate endothelin-1 signaling in neural crest-derived pharyngeal arch mesenchyme. Dev. Biol. 255, 230–237 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Clouthier, D. E. et al. Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice. Dev. Biol. 217, 10–24 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Yanagisawa, H., Clouthier, D. E., Richardson, J. A., Charite, J. & Olson, E. N. Targeted deletion of a branchial arch-specific enhancer reveals a role of dHAND in craniofacial development. Development 130, 1069–1078 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Thomas, T. et al. A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme. Development 125, 3005–3014 (1998).

    CAS  PubMed  Google Scholar 

  112. Charite, J. et al. Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer. Genes Dev. 15, 3039–3049 (2001). References 110 and 112 are two important studies that dissected the molecular pathway downstream of endothelin-1, which is involved in ventral patterning of the first pharyngeal arch. Dlx6 directly regulates the expression of dHAND in response to endothelin-1 signalling from the arch epithelium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bachler, M. & Neubuser, A. Expression of members of the Fgf family and their receptors during midfacial development. Mech. Dev. 100, 313–316 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Abu-Issa, R., Smyth, G., Smoak, I., Yamamura, K. & Meyers, E. N. Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development 129, 4613–4625 (2002).

    CAS  PubMed  Google Scholar 

  115. Neubuser, A., Peters, H., Balling, R. & Martin, G. R. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90, 247–255 (1997).

    Article  CAS  PubMed  Google Scholar 

  116. Tucker, A. S., Yamada, G., Grigoriou, M., Pachnis, V. & Sharpe, P. T. Fgf-8 determines rostral–caudal polarity in the first branchial arch. Development 126, 51–61 (1999).

    CAS  PubMed  Google Scholar 

  117. Grigoriou, M., Tucker, A. S., Sharpe, P. T. & Pachnis, V. Expression and regulation of Lhx6 and Lhx7, a novel subfamily of LIM homeodomain encoding genes, suggests a role in mammalian head development. Development 125, 2063–2074 (1998).

    CAS  PubMed  Google Scholar 

  118. Rivera-Perez, J. A., Mallo, M., Gendron-Maguire, M., Gridley, T. & Behringer, R. R. Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib development. Development 121, 3005–3012 (1995).

    CAS  PubMed  Google Scholar 

  119. Yamada, G. et al. Targeted mutation of the murine goosecoid gene results in craniofacial defects and neonatal death. Development 121, 2917–2922 (1995).

    CAS  PubMed  Google Scholar 

  120. Crossley, P. H. & Martin, G. R. The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121, 439–451 (1995).

    CAS  PubMed  Google Scholar 

  121. Shigetani, Y., Nobusada, Y. & Kuratani, S. Ectodermally derived FGF8 defines the maxillomandibular region in the early chick embryo: epithelial–mesenchymal interactions in the specification of the craniofacial ectomesenchyme. Dev. Biol. 228, 73–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Shigetani, Y. et al. Heterotopic shift of epithelial–mesenchymal interactions in vertebrate jaw evolution. Science 296, 1316–1319 (2002). This important paper offers a comparison of the distribution and function of signalling molecules and downstream homeobox genes in the oral regions of jawed (chick) and jawless (lamprey) vertebrate embryos. It raises interesting issues about the evolution of the mandibular arch in the vertebrate lineage.

    Article  CAS  PubMed  Google Scholar 

  123. Mandler, M. & Neubuser, A. FGF signaling is necessary for the specification of the odontogenic mesenchyme. Dev. Biol. 240, 548–559 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Nissen, R. M., Yan, J., Amsterdam, A., Hopkins, N. & Burgess, S. M. Zebrafish foxi one modulates cellular responses to Fgf signaling required for the integrity of ear and jaw patterning. Development 130, 2543–2554 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Furthauer, M., Reifers, F., Brand, M., Thisse, B. & Thisse, C. sprouty4 acts in vivo as a feedback-induced antagonist of FGF signaling in zebrafish. Development 128, 2175–2186 (2001).

    CAS  PubMed  Google Scholar 

  126. Trokovic, N., Trokovic, R., Mai, P. & Partanen, J. Fgfr1 regulates patterning of the pharyngeal region. Genes Dev. 17, 141–153 (2003). This interesting paper shows that functional inactivation of Fgfr1 in the mouse results in patterning defects of the second pharyngeal arch. The data indicate that Fgfr1 function is required to create a permissive environment for NCC migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sarkar, S., Petiot, A., Copp, A., Ferretti, P. & Thorogood, P. FGF2 promotes skeletogenic differentiation of cranial neural crest cells. Development 128, 2143–2152 (2001).

    CAS  PubMed  Google Scholar 

  128. Richman, J. M., Herbert, M., Matovinovic, E. & Walin, J. Effect of fibroblast growth factors on outgrowth of facial mesenchyme. Dev. Biol. 189, 135–147 (1997).

    Article  CAS  PubMed  Google Scholar 

  129. Hu, D. & Helms, J. A. The role of sonic hedgehog in normal and abnormal craniofacial morphogenesis. Development 126, 4873–4884 (1999).

    CAS  PubMed  Google Scholar 

  130. Niederreither, K., Subbarayan, V., Dolle, P. & Chambon, P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nature Genet. 21, 444–448 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Lohnes, D. et al. Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 120, 2723–2748 (1994).

    CAS  PubMed  Google Scholar 

  132. Kanzler, B., Foreman, R. K., Labosky, P. A. & Mallo, M. BMP signaling is essential for development of skeletogenic and neurogenic cranial neural crest. Development 127, 1095–1104 (2000).

    CAS  PubMed  Google Scholar 

  133. Lee, S. H., Fu, K. K., Hui, J. N. & Richman, J. M. Noggin and retinoic acid transform the identity of avian facial prominences. Nature 414, 909–912 (2001). An important study showing the role of BMP molecules in the development of facial structures. By inhibiting the BMP signalling pathway, the authors induced transformation of the maxillary prominence into a supernumerary frontonasal process.

    Article  CAS  PubMed  Google Scholar 

  134. Mina, M., Wang, Y. H., Ivanisevic, A. M., Upholt, W. B. & Rodgers, B. Region- and stage-specific effects of FGFs and BMPs in chick mandibular morphogenesis. Dev. Dyn. 223, 333–352 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Semba, I. et al. Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2. Dev. Dyn. 217, 401–414 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Barlow, A. J. & Francis-West, P. H. Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 124, 391–398 (1997).

    CAS  PubMed  Google Scholar 

  137. Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R. & de Crombrugghe, B. Sox9 is required for cartilage formation. Nature Genet. 22, 85–89 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. & de Crombrugghe, B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 16, 2813–2828 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bendall, A. J. & Abate-Shen, C. Roles for Msx and Dlx homeoproteins in vertebrate development. Gene 247, 17–31 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. Hu, G., Lee, H., Price, S. M., Shen, M. M. & Abate-Shen, C. Msx homeobox genes inhibit differentiation through upregulation of cyclin D1. Development 128, 2373–2384 (2001).

    CAS  PubMed  Google Scholar 

  141. Satokata, I. & Maas, R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–356 (1994).

    Article  CAS  PubMed  Google Scholar 

  142. van den Boogaard, M. J., Dorland, M., Beemer, F. A. & van Amstel, H. K. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nature Genet. 24, 342–343 (2000).

    Article  CAS  PubMed  Google Scholar 

  143. Satokata, I. et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nature Genet. 24, 391–395 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Wilkie, A. O. et al. Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nature Genet. 24, 387–390 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Kanzler, B., Kuschert, S. J., Liu, Y. H. & Mallo, M. Hoxa-2 restricts the chondrogenic domain and inhibits bone formation during development of the branchial area. Development 125, 2587–2597 (1998).

    CAS  PubMed  Google Scholar 

  146. Wilkie, A. O. & Morriss-Kay, G. M. Genetics of craniofacial development and malformation. Nature Rev. Genet. 2, 458–468 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Cohen, M. M. Jr. Malformations of the craniofacial region: evolutionary, embryonic, genetic, and clinical perspectives. Am. J. Med. Genet. 115, 245–268 (2002).

    Article  PubMed  Google Scholar 

  148. McGinnis, W., Levine, M. S., Hafen, E., Kuroiwa, A. & Gehring, W. J. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 308, 428–433 (1984).

    Article  CAS  PubMed  Google Scholar 

  149. Bridges, C. & Morgan, T. H. The Third Chromosome Group of Mutant Characters in Drosophila melanogaster (Carnegie Institution, Washington DC, 1923).

    Book  Google Scholar 

  150. Lewis, E. B. A gene complex controlling segmentation in Drosophila. Nature 276, 565–570 (1978).

    Article  CAS  PubMed  Google Scholar 

  151. Kmita, M. & Duboule, D. Organizing axes in time and space; 25 years of colinear tinkering. Science 301, 331–333 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Ferrier, D. E. & Holland, P. W. Ancient origin of the Hox gene cluster. Nature Rev. Genet. 2, 33–38 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Graham, A., Papalopulu, N. & Krumlauf, R. The murine and Drosophila homeobox gene complexes have common features of organization and expression. Cell 57, 367–378 (1989).

    Article  CAS  PubMed  Google Scholar 

  154. Duboule, D. & Dolle, P. The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. EMBO J. 8, 1497–1505 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. McGonnell, I. M. & Graham, A. Trunk neural crest has skeletogenic potential. Curr. Biol. 12, 767–771 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Noden, D. M. Craniofacial development: new views on old problems. Anat. Rec. 208, 1–13 (1984).

    Article  CAS  PubMed  Google Scholar 

  157. Chai, Y. et al. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127, 1671–1679 (2000).

    CAS  PubMed  Google Scholar 

  158. Carlson, B. M. Patten's Foundations of Embryology 6th edn (McGraw-Hill Publishing Company, 1996).

    Google Scholar 

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Acknowledgements

We are grateful to S. Metz for help in the preparation of the figures. Work in the authors' laboratory is supported by the European Commission grant Brainstem Genetics, the ARC Association pour la Recherche sur le Cancer, the Ministère pour le Recherche (ACI Program) and by institutional funds from Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale and Hôpital Universitaire de Strasbourg.

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Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Lousis Pasteur, CU de Strasbourg, BP 10142-67404, Illkirch Cedex, France

    Fabio Santagati & Filippo M. Rijli

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  1. Fabio Santagati
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Correspondence to Filippo M. Rijli.

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DATABASES

LocusLink

bapx1

Bmp4

dHand

Dlx1

Dlx2

Dlx3

DLX3

Dlx5

Dlx6

eHand

Eta

Et1

Fgf2

fgf3

Fgf4

Fgf8

Fgfr1

GLI2

Gsc

hand2

hoxa2

Hoxa2

Hoxa3

Hoxa4

hoxb2

Hoxb2

Hoxb4

Hoxc4

Hoxd4

Lhx6

Msx1

Msx2

Noggin

Otx2

PTCH

Ptx1

RAR

sef

Shh

SHH

SIX3

Sox9

sprouty

TWIST

ZIC2

ZFIN

sucker

OMIM

anencephaly

holoprosencephaly

Glossary

DIENCEPHALON

The more posterior of the two subdivisions of the forebrain (the anterior subdivision being the telencephalon). Structures that are derived from the diencephalon include the retina, the pineal gland, the thalamus and the hypothalamus.

FLOOR PLATE

The neural tube has been divided into different regions. The ventral cells closest to the midline constitute the floor plate. The dorsal cells closest to the midline correspond to the roof plate. The alar plate (dorsal) and the basal plate (ventral) lie between these two cell populations, and are separated by the sulcus limitans.

HOMEODOMAIN

A 60-amino-acid DNA-binding domain that comprises three α-helices and is found in many transcription factors.

RETINOIC ACID

A derivative of vitamin A that acts as a morphogen and regulator of differentiation during embryogenesis.

FIBROBLAST GROWTH FACTORS

(FGFs). Multifunctional factors that are involved in embryonic development. More than 20 FGFs and 4 FGF receptors have been described. Their coordinated activity controls cell proliferation, migration, survival and differentiation. FGFs regulate growth and morphogenesis by early action on regional patterning, and a later effect on the growth of progenitor cells of the forebrain.

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis. Wnt proteins bind on the cell surface to receptors of the Frizzled family.

RHOMBOMERES

Neuroepithelial segments found transiently in the embryonic hindbrain that adopt distinct molecular and cellular properties, restrictions in cell mixing, and ordered domains of gene expression.

BONE MORPHOGENETIC PROTEINS

Multifunctional secreted proteins of the transforming growth factor superfamily. In the early embryo, they participate in dorsoventral patterning.

BASIC HELIX–LOOP–HELIX

A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.

CRE RECOMBINASE

Part of a site-specific recombination system derived from Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, leading to excision of the intervening sequence.

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Santagati, F., Rijli, F. Cranial neural crest and the building of the vertebrate head. Nat Rev Neurosci 4, 806–818 (2003). https://doi.org/10.1038/nrn1221

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