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When the neural tube forms after gastrulation, the dorsal side of the tube develops into the neural crest. [1] Cranial neural crest cells (CNCCs) are derived from the most anterior portion of the neural crest. [1] The cells of the neural crest transform through an epithelial-to-mesenchymal transition, allowing them to migrate to other regions of the head and neck.[2] Cranial neural crest cells are able to generate many cell types, including glia, Schwann cells, neurons, bone, pigment cells, muscle cells, cartilage, teeth, and tissues of the thyroid, parathyroid, and thymus. [1] Cranial crest cells possess the unique ability, out of the five neural crest populations (cranial, cardiac, trunk, vagal, and sacral), to generate both bone and neural derivatives. [3]

Migration and Development

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Cranial Neural Crest Cell Migration Pathways in Development

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Cranial neural crest cells (CNCCs) are located in the hindbrain and midbrain regions of the neural tube. The hindbrain is partitioned into 8 regions called rhombomeres. [4] CNCCs migrate ventrally from these regions to contribute to the formation of pharyngeal arches and pouches as well as the frontonasal process.[4]

The migratory pathways of cranial neural crest cells and their contribution to neck and head structures.
Cranial Neural Crest Cell Migration Pathways in Development[4]
Brain Section Migratory Destination Structures that arise
Mesencephalon Frontonasal processes Forehead, nose, primary palate, optic vesicle
Rhombomeres 1 & 2 1st pharyngeal arch Jawbones, incus, malleus, neurons of trigeminal ganglion (innervating teeth and jaw), ciliary ganglion (innervating ciliary muscle of eye), frontonasal process (forehead, middle of nose, primary palate), odontoblasts
Rhombomere 4 2nd pharyngeal arch Hyoid cartilage of the neck, stapes of middle ear, neurons of the facial nerve
Rhombomeres 6 - 8 Pharyngeal arches and pouches 3 & 4 Hyoid cartilage, thymus, parathyroid, parts of the aorta and pulmonary artery, neck muscle attachment to clavicle
Rhombomeres 3 & 5 Undergo apoptosis and do not migrate Abnormal muscle attachment sites, if apoptosis fails to occur

Regulatory Pathways of Cranial Neural Crest Cells

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Many factors are required for the formation of the neural crest. In order for an embryo to develop successfully, cranial neural crest cells and factors associated with it must work together at a designated location and perform their function at the right time, amount, and direction.[5] Processes that regulate migration include chemotaxis, which drives directional movement of cranial neural crest cells, and concentration gradients that regulate the number of cranial crest cells that migrate to a specific location.[5] One example of factors involved in cranial crest migration and proliferation are those of the BMP family. High levels of BMPs lead to the formation of a more prominent frontonasal process and maxillary prominence, while lower levels lead to reduced growth of these structures;[4] for instance, dogs express more BMP than humans in facial development and thus have a larger and more prominent nose and muzzle region.

The factor FoxD3 activates the formation of the neural crest in a controlled manner; without FoxD3, neural crest differentiation is inhibited.[6] FoxD3 is also needed for the expression of cell surface proteins that allow cell migration.[6] The factor Sox9 prevents neural crest cells from undergoing apoptosis as they delaminate, and both Sox9 and Snail factors are needed for the cells to become neural crest-like and survive through the epithelial-to-mesenchymal transition.[6] In mice, the factor p53 is essential in coordinating cranial neural crest cell growth and regulating the effects of Snail.[2] Also, without p53, Sox9 is severely down-regulated.[2] Small G proteins such as Rho GTPase allow cells to change shape as well as giving them migratory abilities.[4] Neural crest specifiers also activate cell surface receptors such as receptor tyrosine kinase Ret and Kit to allow neural crest cells to respond to patterning and inducing proteins in their environment.[4] BMP and Wnt direct rostral migration of cranial neural crest cells to form the frontonasal and maxillary prominences; Wnt regulates the effects of BMP.[4] Sclerostin domain-containing 1 (Sostdc1) is also a regulator of BMP.[7] When transcribed excessively, it will inhibit BMP function.[7] Sostdc1 itself is regulated by Pax-3, as increasing expression of Pax-3 causes an increase in Sostdc1 expression.[7] TGF-β 3 is a factor that plays a major role in the formation and fusion of the palate. Abnormalities in this factor and its function result in the palate being unable to fuse, causing conditions such as cleft palate.[8]

Cranial Neural Crest Cell Regulatory Factors and Functions[2][4][5][6][7][8]
Factor Function
FoxD3 Regulates formation of neural crest cells and cell migration
Sox9 Mesenchymal transition
Snail Mesenchymal transition
p53 Coordinating cranial neural crest cell growth and regulating Snail factor
Small G proteins (Rho GTPase) Change shape of cells, migratory abilities
Neural crest specifiers Allows neural crest cells to respond to patterning
Pax-3 Regulates Sclerostin domain-containing 1 (Sostdc1)
Sclerostin domain-containing 1 (Sostdc1) Inhibits BMP
BMP Formation of frontonasal and maxillary prominences
Wnt Formation of frontonasal and maxillary prominences, regulates BMP
Sonic hedgehog (Shh) Formation of frontonasal processes
Fgf8 Facial morphogenesis, formation of frontonasal processes
TGF-Beta 3 Apoptosis for palate fusion and formation

Arrival and Specification

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Many cell types and tissues of the head and neck are formed from the cranial neural crest after migration from the rhombomeres and midbrain regions. Specifically, the facial bones and cartilage, neck cartilage, cranial nerves, jaw, teeth, and palate all develop from the cranial crest, with contributions from other surrounding cell populations.[3] Additionally, complex structures such as the eye and ear require cranial neural crest cells for bone development and regulation of growth.[3]

Development of Cranial Nerve Ganglia

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The process of cephalic gangliogenesis, or the formation of the cranial ganglia, is dependent upon the interaction between epidermal placodes and cranial neural crest cells.[9] The epidermal placodes are formed in the overlying epidermis via reciprocal induction interactions with the underlying pharyngeal pouches.[9] The placodes then separate from the surface ectoderm and interact with cranial neural crest cell subpopulations, which have already migrated into the area, to form cranial nerve ganglia.[9] Cranial neural crest cells contribute to the proximal elements of the ganglia of cranial nerve V, IX, and X and to the rudimentary proximal ganglia of cranial nerve VII prior to fusion with the entirely ectodermally derived ganglia of cranial nerve VIII during development.[10] [9] The distal elements of these nerve ganglia are formed by contributions from the placodal ectodermal cells.[10] The dual ectoderm and neural crest origin of cranial ganglia is in contrast to the rest of the body where autonomic ganglia are strictly neural crest in origin, however the glial cells are still solely neural crest derived in the head and therefore cranial neural crest cells do contribute at least in part to the function of all of the cranial nerves via the supportive glial cells.[9]

The process of neurogenesis (formation of nerve ganglia) in the cranial neural crest cells seems to be dependent upon Bmp2 and Bmp4 signaling, as inhibition of this signaling leads to cranial nerve ganglia lacking proximal elements, which are normally formed by the neural crest.[10] The Wnt proteins, which are able to induce stem cells to begin proliferation, have also been hypothesized to perform a role in neurogenesis.[11] Wnt proteins induce the activation of the β-catenin pathway in the neural crest cells, directing the cells towards the sensory neuronal fate, subsequently increasing the population of neural progenitor cells in tissues destined to form neurons.[11] Targeted inhibition of the β-catenin signaling in cranial neural crest cells results in a cell population that can undergo normal proliferation but is inhibited from forming sensory nerve ganglia, demonstrating the importance of β-catenin signaling in neuron formation in neural crest cells.[11]

Eye Formation

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The development of the eye is dependent on interactions of epithelial layers with the lens vesicle and mesenchymal cranial crest cells. Cranial crest cells migrate into the space between the optic cup and the lens vesicle, condensing and flattening into the cornea and scleral bones in response to collagen produced by the overlying ectodermal epithelium, which in turn is activated by the growing lens vesicle. [3] The cornea and scleral bones together regulate fluid pressure in the eye.[12] The lens vesicle produces the factor Mitf in response to activin-like factors produced by cranial crest cells, which activates pigmentation genes in the developing retina.[12] The crest derivatives are also important for the maintenance of expression of eye development factors throughout development and adulthood, such as Pax6, a factor important in wound healing and responsible for the continual regeneration of corneal tissue. The cornea maintains a stem cell population of neural crest origin that provides precursors for corneal repair.[13]

Bone and Cartilage Formation

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Potential for bone and cartilage formation is a special property of cranial crest cells distinguishing them from other types of neural crest.[3] All bones of the head, with the exception of the back of the skull, are derived from cranial crest, and the mechanism of bone formation from cranial crest is different from that of mesodermal bone formation.[3] Formation of both cartilage and bone from cranial crest begins with BMP signals received from the overlying epidermis; lower and higher levels of BMPs result in potential bone precursors (chondrocyte-like osteoblasts) and cartilage (chondrocytes) respectively.[3] Chondrocyte-like osteoblasts begin producing the protein osteopontin and then the protein Indian hedgehog through an autocrine pathway, which leads to commitment as a bone precursor cell, or osteocyte.[3] Thus, crest cells commit to becoming bone precursors faster in the presence of large numbers of other bone precursors. Committed bone precursors secrete calcium-binding collagen, forming a calcified matrix and building bone one layer at a time.

Neck Cartilage Formation

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Cranial neural crest cells form most of the skeleton of the head and neck region of vertebrates. As seen in adult mice, neural crest derivatives present in this region are extensive, forming bone, cartilage, and connective tissue.[14] Some of the more prevalent structures of cranial neural crest origin include the pharynx and larynx constrictors, as well as the thyroid, cricoid, and arytenoid cartilages and the attachment sites for their associated musculature.[14] The cranial neural crest also contributes to the attachment sites for the trapezius, the sternocleidomastoid, and the facial sling of the omohyoid branchial muscles, as well as forming all of the connective tissue of the tongue musculature, which itself is mesodermally derived.[14] The most posterior extent of the cranial neural crest contribution in the neck region appears to be the branchial muscle attachment sites on the shoulder girdle.[14] The thyroid, cricoid, and arytenoid cartilages are formed via chondrogenesis (formation of cartilage) by the neural crest cells.[10] However, these cells do not display this potential, or the potential to produce bone, when they are isolated in culture.[10] Specific reciprocal induction interactions in the embryo are required for the cranial neural crest cells to form either cartilage or bone, which seem to be dependent upon the spatial and temporal location of the cells.[10] Some of these interactions have been hypothesized to involve the BMP (Bone Morphogenetic Protein) family. Bmp2 and Bmp4 in particular have been implicated in the development of the posterior cartilage elements, as inhibition of Bmp2 and Bmp4 signaling leads to the complete or partial absence of the thyroid, cricoid, and arytenoid cartilages.[10]

Development of Frontonasal Process

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The frontonasal process forms the forehead, nose, and primary palate and is derived from non-Hoxa2-expressing cranial crest cells (those that migrate from regions anterior to rhomobmere 3) as well as other mesenchymal and ectodermal cells.[3] The precise role of each cell type in the determination of the structures of the face is not completely understood, but crest cells are key players in directing cell fate. A proposed signaling centre of the frontonasal process, the frontonasal ectodermal zone, bounds domains of Shh and Fgf expression in the ectoderm, and causes differential expression of BMPs in cranial neural crest, which in turn regulate the rate of growth in their immediate area.[15] In chimeric transplantation experiments, cranial neural crest taken from a duck and introduced to a quail embryo in the frontonasal process causes the formation of a duck beak, while the reverse transplantation causes the formation of a quail beak in a duck embryo.[16] The crest is also responsible for forming the bones, cartilage, and general shape of the face. Here, elevated Wnt protein levels cause cranial crest cells to increase proliferation, while the overlying ectodermal cells are unable to respond to Wnt and do not increase proliferation.[17] The precise regulation of Wnt secretion and Wnt receptors in cranial crest cells determine the shape of the face within a particular species.[17] However, the ectodermal epithelium surrounding the frontonasal process secretes Fgf8 on its dorsal (inner) side and Shh on its ventral (outer) side, specifying the dorsal-ventral axis of the face.[17]

Palate Formation

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Palate development occurs at the interface between two populations of cranial crest cells. Crest cells belonging to the frontonasal process contribute to the primary palate, while cells from the first pharyngeal arch contribute to the both the primary and secondary palate, which fills in the spaces around the primary palate that occur as an embryo grows.[3] The fusion of structures from these two sources relies on Fgf signaling between the cranial crest mesenchyme and the overlying ectoderm, as well as the presence of TGF-beta-3.[18]

Jaw Formation

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In the developing jaw, cranial crest cells from the first pharyngeal arch are responsible for bone formation.[3] These cells express proteins from the Dlx family at varying levels, precisely controlling growth and cell fate in different regions of the jaw. The surrounding ectoderm maintains expression of the correct factors in the crest cells by changing expression of Fgf8 and various BMPs, resulting in a complex balance of factors needed for proper jaw formation.[19]

Tooth Formation

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Cranial crest cells from the first pharyngeal arch form the odontoblasts, inner cells of the tooth that secrete dentin.[3] Other cranial crest cells induce the formation of the enamel knot from the surrounding epithelium. The enamel knot, a signaling centre found in each tooth, regulates levels of Shh, Fgf4, and several BMPs in order to precisely control tooth shape.[3]

Development of Middle Ear Structures

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Formation of the ossicles and tympanic ring of the middle ear results from the interaction of specific cranial neural crest cells, overlying ectoderm, and pharyngeal endoderm. In mammals, the cranial crest cells of pharyngeal arch 2, distinguished by Hoxa2 expression starting before their migration to the arch, form the stapes, after receiving retinoic acid signals from the surrounding tissue.[3] Other cranial crest cells from the first pharyngeal arch become the incus, malleus, and tympanic ring and require Endothelin1, produced by the overlying ectoderm, to begin differentiation.[20] The transcription factors Dlx2 and Prx1 must also be produced by ossicle-forming crest cells for successful middle ear development; these factors are upregulated by the presence of Endothelin1 and Fgf8 secreted by the overlying ectoderm.[20] In vertebrates other than mammals, only one ossicle, the columella, is present; this bone forms from the crest of the second pharyngeal arch and is analogous to the stapes.[21]

Development of Thymus

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Cranial neural crest cells play a key role in the development of the thymus, a glandular organ that forms from the pharynx.[22] The thymus is first evident as a local proliferation of cells in the posterior of pharyngeal arch 3, resulting in the formation of two thymus primordia that subsequently migrate ventrally and fuse at the throat midline.[22] Cranial neural crest cells are found in the interlobular spaces and in the medulla of the adult thymus and are required, along with the pharyngeal endoderm, early in development for the induction of lymphoid stem cells, which travel through the blood to the thymus, to differentiate into thymocytes (progenitor cells), which is an essential step in the production of a functional thymus gland.[23] The cranial neural crest cells that contribute to the development of the thymus are from the 3rd and 4th pharyngeal arches.[23] The expression of the Pax-3 transcription factor in the endodermal tissue around pharyngeal arch 3 has been shown to play an important role in thymus development, as demonstrated by the fact that Pax-3 mutants display partial or complete absence of the thymus gland. [22] This continued expression of Pax-3 throughout thymus formation is maintained by the expression of the gene Hoxa-3, part of the Hox gene family, which has been hypothesized to affect the differentiation and induction ability of cranial neural crest cells.[22]

Development of Thyroid and Parathyroid

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Cranial neural crest cells also contribute substantially to the development of the thyroid, another glandular pharyngeal organ.[22] The thyroid forms via the fusion of two structures of different germ layer origin, the endodermal derived thyroid diverticulum, which forms out of the pharynx, and the ectodermally derived ultimobranchial body, which in large part is composed of cranial neural crest cells,[24] supplied by the mesenchyme of the 4th pharyngeal arch.[22] The complete thyroid forms when these two independent structures migrate to the thyroid’s final position in the embryo and fuse, mixing together the endodermal and ectodermal cells.[22] In the fully formed thyroid, cranial neural crest cells differentiate to form the parafollicular cells, also known as C-cells, which secrete the polypeptide hormone calcitonin.[22] The fusion of the ultimobranchial body and the thyroid diverticulum has been hypothesized to be a result of the mutual expression of the gene Hoxa-3 in the cells of both structures, as well as in the surrounding endoderm.[22] Failure of the two structures to fuse has been observed in Hoxa-3 mutants, indicating a role of the gene in the cellular recognition or induction capability of the cranial neural crest cells, the main component of the ultimobranchial body.[22]

In addition to the thyroid, cranial neural crest cells also contribute to the development of the parathyroid glands, which are derived as well from the 4th pharyngeal arch.[23] Cranial neural crest cells form the connective tissues between the cords of the parathyroid cells in the adult parathyroid glands.[23]

Development of Heart Outflow Structures

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In addition to pharyngeal glands, cranial neural crest cells also contribute to various structures of the circulatory system. Neural crest cells populate the pharyngeal arches and form the mesenchymal walls of the aortic arches, transient blood vessels present during development.[25] At a later stage in development, when the formation of the heart has commenced, the cranial neural crest derived mesenchyme migrates to the outflow regions of the heart.[25] Cranial neural crest cells have been shown to contribute to the formation of septa, in particular the aorticopulmonary and conotruncal septa, which separate the aorta from the pulmonary artery, and the internal conus arteriosus, respectively.[25] Therefore defects in the migration or integration of cranial neural crests cells can cause serious circulatory problems associated with non-functional septa.[25] Even though the contributions of the neural crest cells to the heart outflow are known, the specific interactions and mechanisms of differentiation and integration remain largely unknown.[25] The cranial neural crest cell populations that contribute directly to the formation of the heart structures originate in pharyngeal arches 3, 4, and 6, with cells from the 4th pharyngeal arch outnumbering the contributions from the other two arches by a ratio of 4:1.[25] Pharyngeal arches 1 and 2 also influence the development of the circulatory system, as neural crest derived mesenchymal cells from these arches form the walls of the aortic arches early in development which then give rise to subsequent vessels that have remnant neural crest contributions to their walls, such as the systemic aorta, common carotids, and brachiocephalic trunks.[25] [26]

Other Significance

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Effects of Cranial Crest on the Brain

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Recently, cranial crest cells in the facial skeleton were discovered to be essential for the development of the forebrain, specifically the telencephalon. The outer ectodermal layer of the head produces BMP4, which blocks the synthesis of Fgf8 in the neural ectoderm needed for forebrain development.[27] By producing factors including Gremlin and Noggin that inactivate BMP4, the cranial crest cells present between the two ectodermal layers preserve the forebrain’s ability to grow despite antagonizing signals from the surface ectoderm.[27]

Stem Cell Potential

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Given the wide range of cell types that emerge from the neural crest, many researchers are curious about the stem cell potential of various cranial neural crest derivatives. Several types of neural crest stem cell (NCSC) of cranial neural crest origin have been isolated from both adult and embryonic tissues, including embryonic NCSCs, skin-derived precursors (SKPs), corneal stem cells, and dental pulp stem cells.[28] Taken from adult organisms, corneal stem cells are able to generate neurons, adipocytes, and chondrocytes ‘’in vitro’’, while dental pulp stem cells can generate adipocytes, neurons, chondrocytes and melanocytes ‘’in vitro’’.[13] [29] [30]

Possible Therapeutic Use in Cleft Palate Repair

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Cranial neural crest cells have a great potential to differentiate into numerous cell types.[1] They also normally migrate into head regions (including the primary palate) in development.[2] This would mean that no "new" type of cells are placed in an area where they do not usually belong, minimizing the chances of something else entirely different proliferating in the target palate area. Cranial neural crest cells are also a better candidate than other neural crest cells in that they are the only ones capable of forming bone.[4] Also, they are able to induce the expression of the same factors in surrounding CNCCs as they themselves express, through autocrine signaling pathways. Some CNCCs do not have Hox gene expression, giving them their bone forming abilities.[4] In contrast, trunk neural crest cells do express Hox genes and have lost bone forming capabilities.[4]

Cleft palate cases of various severity affect about 1 in 700 children born worldwide.[31] It is a considerable concern in young children and babies, as it can significantly affect the child's feeding abilities as well as the child's eyes, ears, nose and cheeks.[31] Ear development can also be affected and can later result in recurring ear infections.[31] The current form of repair usually requires multiple surgical procedures carried out as the child grows.[31] The process is long and quite painful, and there is a possibility that the repaired cleft can reopen due to extensive scar tissue from the surgery preventing the tissue from integrating sufficiently.[31]

Using cranial neural crest cells to partially grow the palate and perhaps even induce the surround cells to proliferate would be a much less invasive and time conserving procedure. Adding factors like sonic hedgehog (Shh) and BMP could induce the growth of the bony palate and the soft palate. Research has found that these two factors induced maxillary growth even when placed just on the surface of the tissue, with no injection being necessary. [32] These factors could be placed along with growth mediums on a retainer-like apparatus that is fitted to the child's facial structure. The retainer would act both as a scaffold for the new cells to grow on and also as a protection from tongue movements or objects placed in the mouth that could possibly disturb cell growth.

When the two palate plates have grown enough so that they are touching, factor TGF-β 3 should be added in order to induce the apoptosis that must happen before the plates can fuse.[8] The benefits of using TGF-β 3 lie in the fact that it is no longer produced once the plates fuse, so excessive apoptosis that could lead to the cleft reopening is unlikely.[8]

Notes

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  1. ^ a b c d Santagati, F., & Rijli, F. M. (2003). Cranial neural crest and the building of the vertebrate head. Nature Reviews. Neuroscience, 4(10), 806-818. doi: 10.1038/nrn1221
  2. ^ a b c d e Rinon, A., Molchadsky, A., Nathan, E., Yovel, G., Rotter, V., Sarig, R., & Tzahor, E. (2011). p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes. Development (Cambridge, England), 138(9), 1827-1838. doi: 10.1242/dev.053645
  3. ^ a b c d e f g h i j k l m n Gilbert, Scott F. (2010). ‘’Developmental Biology, Ninth Edition’’. Sunderland, MA, USA: Sinauer Associates, Inc.
  4. ^ a b c d e f g h i j k Gilbert, S. F. (2010). Developmental Biology. MA, USA: Sinauer Associates.
  5. ^ a b c Kulesa, P. M., Bailey, C. M., Kasemeier-Kulesa, J. C., & McLennan, R. (2010). Cranial neural crest migration: New rules for an old road. Developmental Biology, 344(2), 543-554. doi: 10.1016/j.ydbio.2010.04.010
  6. ^ a b c d Morris-Kay, G., & Tan, S. (1987). Mapping cranial neural crest cell migration pathways in mammalian embryos. Trends in Genetics, 3, 257-261. doi: 10.1016/0168-9525(87)90260-5
  7. ^ a b c d Wu, M., Li, J., Engleka, K. A., Zhou, B., Lu, M. M., Plotkin, J. B., & Epstein, J. A. (2008). Persistent expression of Pax3 in the neural crest causes cleft palate and defective osteogenesis in mice. The Journal of Clinical Investigation, 118(6), 2076-2087. doi: 10.1172/JCI33715
  8. ^ a b c d Ito, Y., Yeo, J. Y., Chytil, A., Han, J., Bringas, P., Nakajima, A., et al. (2003). Conditional inactivation of Tgfbr2 in cranial neural crest causes palate and calvaria defects. Development , 5269-5280.
  9. ^ a b c d e Le Douarin, N. M., Fontaine-Perus, J., & Couly, G. (1986). Cephalic ectodermal placodes and neurogenesis. ‘’Trends in Neurosciences’’ , 9, 175-180.
  10. ^ a b c d e f g Kanzler, B., Foreman, R. K., Labosky, P. A., & Mallo, M. (2000). BMP signaling is essential for the development of skeletogenic and neurogenic cranial neural crest. ‘’Development’’ , 1095-1104.
  11. ^ a b c Lee, H. Y., Kleber, M., Hari, L., Brault, V., Suter, U., Taketo, M. M., et al. (2004). Instructive Role of Wnt/B-Catenin in Sensory Fate Specification in Neural Crest Stem Cells. ‘’Science’’ , 303, 1020-1023.
  12. ^ a b Fuhrmann S, EM Levine, TA Rehr (2000). “Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick”. ‘’Development ‘’ ‘’’127’’’, 4599-4609
  13. ^ a b Yoshida S et al. (2006). “Isolation of multipotent neural crest-derived stem cells from the adult mouse cornea”. ‘‘Stem Cells’’ ‘’’24’’’, 2714–2722. DOI 10.1002/dvdy.20833
  14. ^ a b c d Matsuoka, T., Ahlberg, P. E., Kessaris, N., Iannarelli, P., Dennehy, U., Richardson, W. D., et al. (2005). Neural crest origins of the neck and shoulder. ‘’Nature’’ , 436, 347-355.
  15. ^ Hu D, and RS Marcucio. (2009). “Unique organization of the frontonasal ectodermal zone in birds and mammals”. ‘’Developmental Biology’’ ‘’’325(1)’’’, 200-210. DOI 10.1016/j.ydbio.2008.10.026
  16. ^ Schneider RA, and JA Helms (2003). “The cellular and molecular origins of beak morphology”. ‘’Science’’ ‘’’299’’’, 565 -568
  17. ^ a b c Brugmann SA, et al. (2007). “Wnt signaling mediates regional specification in the vertebrate face”. ‘’Development’’ ‘’’134(18)’’’, 3283-95. DOI 3283-3295 10.1242/dev.005132
  18. ^ San Miguel S, et al. (2011). “Ephrin reverse signaling controls palate fusion via a PI3 kinase-dependent mechanism”. ‘’Developmental Dynamics’’ ‘’’240(2)’’’, 357-64. DOI 10.1002/dvdy.22546
  19. ^ Chai Y, RE Maxson (2006). “Recent advances in craniofacial morphogenesis”. ‘‘Developmental Dynamics’’ ‘’’235(9)’’’, 2353-2375. DOI 10.1002/dvdy.20833
  20. ^ a b Mallo M (2001). “Formation of the middle ear: Recent progress on the developmental and molecular mechanisms”. ‘Developmental Biology’’ ‘’’231’’’, 410-419. DOI 10.1006/dbio.2001.0154
  21. ^ Wood JL, et al. (2010). “Analysis of chick (Gallus gallus) middle ear columella formation”. ‘’BMC Developmental Biology’’ ‘’’10(16)’’’. DOI 10.1186/1471-213X-10-16
  22. ^ a b c d e f g h i j Manley, N. R., & Capecchi, M. R. (1995). The role of Hoxa-3 in mouse thymus and thyroid development. ‘’Development’’ , 121, 1989-2003.
  23. ^ a b c d Bockman, D. E., & Kirby, M. L. (1984). Dependence of thymus development on derivatives of the neural crest. ‘’Science’’ , 223 (4635), 498-500.
  24. ^ Manley, N. R., & Capecchi, M. R. (1998). Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. ‘’Developmental Biology’’ , 195, 1-15.
  25. ^ a b c d e f g Phillips, M. T., Kirby, M. L., & Forbes, G. (1987). Analysis of cranial neural crest distribution in the developing heart using quail-chick chimeras. ‘’Circulation Research’’ , 60 (1), 27-30.
  26. ^ Le Lievre, C. S., & Le Douarin, N. M. (1975). Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. ‘’Journal of Embryology’’ , 34 (1), 125-154.
  27. ^ a b Le Douarin NM et al. (2007). “Role of the neural crest in face and brain development”. ‘‘Brain Research Review’’ ‘’’55(2)’’’, 237-47.
  28. ^ Shakhova O and L Sommer (2010). “Neural crest-derived stem cells, StemBook, ed.”. The Stem Cell Research Community, StemBook. DOI 10.3824/stembook.1.51.1
  29. ^ Stevens A et al. (2008). “Human dental pulp stem cells differentiate into neural crest-derived melanocytes and have label-retaining and sphere-forming abilities”. ‘‘Stem Cells and Development’’ ‘’’17’’’, 1175–1184.
  30. ^ Gronthos S et al. (2002). “Stem cell properties of human dental pulp stem cells”. ‘‘Journal of Dental Research’’ ‘’’81’’’, 531–535.
  31. ^ a b c d e Cleft lip and palate. (n.d.). In Wiki. Retrieved November 17, 2012, from http://en.wikipedia.org/wiki/Cleft_lip_and_palate
  32. ^ Zhang, ZY, YQ Song, X Zhao et al. (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(17)’’’, 4135-4146.
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