Pharyngeal Arch Derivatives Research Articles

Onco-Ontogeny of Squamous Cell Cancer of the First Pharyngeal Arch Derivatives.

Head and neck squamous cell carcinoma (H&NSCC) is an anatomic, biological, and genetic complex disease. It involves more than 1000 genes implied in its oncogenesis; for this review, we limit our search and description to the genes implied in the onco-ontogeny of the derivates from the first pharyngeal arch during embryo development. They can be grouped as transcription factors and signaling molecules (that act as growth factors that bind to receptors). Finally, we propose the term embryo-oncogenesis to refer to the activation, reactivation, and use of the genes involved in the embryo's development during the oncogenesis or malignant tumor invasion and metastasis events as part of an onco-ontogenic inverse process.

Trick or teeth? A peculiar cause of deafness

Abnormal development of specific first pharyngeal arch derivatives can result in ectopic teeth which can develop inside the middle ear causing hearing loss. This case is about an 11-year-old patient with hearing loss in the left ear caused by an ectopic tooth in the middle ear.

Conductive Hearing Loss in Children.

A variety of congenital and acquired disorders result in pediatric conductive hearing loss. Malformations of the external auditory canal are invariably associated with malformations of the middle ear space and ossicles. Isolated ossicular malformations are uncommon. Syndromes associated with external and middle ear malformations are frequently associated with abnormal development of first and second pharyngeal arch derivatives. Chronic inflammatory disorders include cholesteatoma, cholesterol granuloma, and tympanosclerosis.

Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies.

Outflow tract abnormalities are the most frequent congenital heart defects. These are due to the absence or dysfunction of the two main cell types, i.e., neural crest cells and secondary heart field cells that migrate in opposite directions at the same stage of development. These cells directly govern aortic arch patterning and development, ascending aorta dilatation, semi-valvular and coronary artery development, aortopulmonary septation abnormalities, persistence of the ductus arteriosus, trunk and proximal pulmonary arteries, sub-valvular conal ventricular septal/rotational defects, and non-compaction of the left ventricle. In some cases, depending on the functional defects of these cells, additional malformations are found in the expected spatial migratory area of the cells, namely in the pharyngeal arch derivatives and cervico-facial structures. Associated non-cardiovascular anomalies are often underestimated, since the multipotency and functional alteration of these cells can result in the modification of multiple neural, epidermal, and cervical structures at different levels. In most cases, patients do not display the full phenotype of abnormalities, but congenital cardiac defects involving the ventricular outflow tract, ascending aorta, aortic arch and supra-aortic trunks should be considered as markers for possible impaired function of these cells. Neural crest cells should not be considered as a unique cell population but on the basis of their cervical rhombomere origins R3-R5 or R6-R7-R8 and specific migration patterns: R3-R4 towards arch II, R5-R6 arch III and R7-R8 arch IV and VI. A better understanding of their development may lead to the discovery of unknown associated abnormalities, thereby enabling potential improvements to be made to the therapeutic approach.

Early development of the malleus and incus in humans.

It is widely accepted by developmental biologists that the malleus and incus of the mammalian middle ear are first pharyngeal arch derivatives, a contention based originally on classical embryology that has now been backed up by molecular evidence from rodent models. However, it has been claimed in several studies of human ossicular development that the manubrium of the malleus and long process of the incus are actually derived from the second arch. This 'dual-arch' interpretation is commonly presented in otolaryngology textbooks, and it has been used by clinicians to explain the aetiology of certain congenital abnormalities of the human middle ear. In order to re-examine the origins of the human malleus and incus, we made three-dimensional reconstructions of the pharyngeal region of human embryos from 7 to 28 mm crown-rump length, based on serial histological sections from the Boyd Collection. We considered the positions of the developing ossicles relative to the pharyngeal pouches and clefts, and the facial and chorda tympani nerves. Confirming observations from previous studies, the primary union between first pharyngeal pouch and first cleft found in our youngest specimens was later lost, the external meatus developing rostroventral to this position. The mesenchyme of the first and second arches in these early embryos seemed to be continuous, but the boundaries of the developing ossicles proved to be very hard to determine at this stage. When first distinguishable, the indications were that both the manubrium of the malleus and the long process of the incus were emerging within the first pharyngeal arch. We therefore conclude that the histological evidence, on balance, favours the 'classical' notion that the human malleus and incus are first-arch structures. The embryological basis of congenital ossicular abnormalities should be reconsidered in this light.

The sonic hedgehog signaling pathway and the development of pharyngeal arch Derivatives in Haplochromis piceatus, a Lake Victoria cichlid

ObjectivesPharyngeal arches develop in the head and neck regions, and give rise to teeth, oral jaws, the hyoid bone, operculum, gills, and pharyngeal jaws in teleosts. In this study, the expression patterns of genes in the sonic hedgehog (shh), wnt, ectodysplasin A (eda), and bone morphogenetic protein (bmp) pathways were investigated in the pharyngeal arches of Haplochromis piceatus, one of the Lake Victoria cichlids. Furthermore, the role of the shh pathway in pharyngeal arch development in H. piceatus larvae was investigated. MethodsThe expression patterns of lymphocyte enhancer binding factor 1 (lef1), ectodysplasin A receptor (edar), shh, patched 1 (ptch1), bmp4, sp5 transcription factor (sp5), sclerostin domain containing 1a (sostdc1a), and dickkopf 1 (dkk1) were investigated in H. piceatus larvae by in situ hybridization. The role of the shh pathway was investigated through morphological phenotypic characterization after its inhibition. ResultsWe found that lef1, edar, shh, ptch1, bmp4, dkk1, sostdc1a, and sp5 were expressed not only in the teeth, but also in the operculum and gill filaments of H piceatus larvae. After blocking the shh pathway using cyclopamine, we observed ectopic shh expression and the disappearance of ptch1 expression. After six weeks of cyclopamine treatment, an absence of teeth in the oral upper jaws and a poor outgrowth of premaxilla, operculum, and gill filaments in juvenile H. piceatus were observed. ConclusionsThese results suggest that the shh pathway is important for the development of pharyngeal arch derivatives such as teeth, premaxilla, operculum, and gill filaments in H. piceatus.

A Model of the Anterior Esophagus in Snakes, with Functional and Developmental Implications

The gross anatomy of the mouth of snakes has always been interpreted as an evolutionary response to feeding demands. In most alethinophidian species, their anatomy allows limited functional independence of right and left sides and the roof and floor of the mouth as well as wide separation of the tips of the mandibles. However, locations of the tongue and glottis in snakes suggest extraordinary rearrangement of pharyngeal structures characteristic of all vertebrates. Serial histological sections through the heads of a number of colubroid species show muscularis mucosal smooth muscle fibers appearing in the paratracheal gutter of the lower jaw at varying levels between the eye and ear regions. Incomplete muscularis externa elements appear beneath the paratracheal gutter more caudally but typically at otic levels. Both muscle layers encompass more of the gut wall at more posterior levels, encircling the gut at the level of the atlas or axis. The pattern in snakes suggests developmental dissociation of dorsal and ventral splanchnic derivatives and extensive topological rearrangements of some ventral pharyngeal arch derivatives typical of most tetrapods. When snakes swallow large prey, the effective oral cavity becomes extremely short ventrally. The palatomaxillary arches function as ratchets packing the prey almost directly into the esophagus. Our findings raise questions about germ layer origins and regulation of differentiation of gut regions and derivatives in snakes and suggest that significant aspects of the evolution of lepidosaurs may be difficult to recover from bones or molecular sequence data alone.

Expression of the Foxi2 and Foxi3 transcription factors during development of chicken sensory placodes and pharyngeal arches

Foxi2 and Foxi3 are members of the Foxi class of Forkhead transcription factors. The Foxi transcription factor family has been shown to play roles in the development of the inner ear and pharyngeal arch derivatives in zebrafish. We describe the expression of Foxi2 and Foxi3 in chicken embryos during the first three days of embryonic development. Foxi3 is initially expressed broadly in the pre-placodal ectoderm surrounding the neural plate, which will give rise to all craniofacial sensory organs. It then becomes restricted to a region immediately anterior to the first pair of somites that will give rise to the otic and epibranchial placodes, before becoming down-regulated from this region and restricted to the ectoderm and endoderm of the pharyngeal arches. In contrast, Foxi2 is initially expressed broadly in cranial ectoderm with the striking exception of the otic placode, and ultimately becomes restricted to pharyngeal arch ectoderm. These expression patterns provide an insight into the roles of these transcriptional regulators during the development of the inner ear and pharyngeal arch derivatives.

Prestyloid compartment of the parapharyngeal space: a histological study using late-stage human fetuses

Although the prestyloid space is well known, its definition still remains unclear. Using semiserial sagittal sections of 15 late-stage human fetal heads, we studied details of the topographical anatomy. A definite posterior marginal fascia of the space was seen along the anterior aspect of the stylopharyngeus and styloglossus muscles. Inferiorly, the prestyloid space faced the bucallis and medial pterygoid muscles and the submandibular gland. The external carotid artery ran along the posterolateral side of the space. The tensor veli palatini fascia did not contribute to the posterior marginal fascia. A major supplying artery of the space was the ascending palatine artery. The prestyloid compartment of the parapharyngeal space (hereafter, the prestyloid space) seems to correspond to a border between the first and second pharyngeal arch derivatives. This concept may provide a better understanding of prestyloid space.

Tracheobronchial anomalies in chromosome 22q11.2 microdeletion

The 22q11.2 microdeletion syndrome consists of several manifestations including congenital heart defects (CHD), velopharyngeal insufficiency, cleft palate, thymus aplasia-hypoplasia, craniofacial anomalies, and hypoparathyroidism. These phenotypic features can occur in many combinations, and the clinical spectrum varies greatly in severity, ranging from life-threatening problems to hypernasal speech [Ryan et al., 1997]. Phenotypic variability is a striking aspect of the 22q11.2 microdeletion and to date the basis of it remains unclear [Yamagishi, 2002]. The 22q11.2 deletion syndrome encompasses the DiGeorge anomaly (DGA), velocardiofacial (VCFS) and conotruncal anomaly face syndromes (CAFS). In addition to the main clinical features several other defects have been reported with the syndrome, including learning difficulties and psychiatric disorders, eye defects, renal and urological anomalies [Wilson et al., 1993; Devriendt et al., 1996; Hong, 1998; Scambler, 2000]. The 22q11.2 microdeletion syndrome, with an incidence of 1/4,000 live births, is the most frequent interstitial deletion known in humans [Scambler, 2000]. Most of 22q11.2 microdeletions are due to ‘‘de novo’’ mutations while from 12% up to 28% are inherited [Rayan et al., 1997; Vantrappen et al., 1999]. It is suggested that it represents a ‘‘contiguous gene syndrome’’ in which many genes can be lost in several more or less visible deletions [Hall, 1993]. Isolated cases of DGA with no microdeletion (12%) may be ascribed to epigenetic factors such as alcohol or retinoic acid ingestion during pregnancy and maternal diabetes [Driscoll et al., 1993]. Structures primarily affected in 22q11.2 patients are derivatives of pharyngeal arches, pharyngeal arch arteries, and the conotruncal region of the heart (craniofacial features, thyroid, parathyroid, thymus, aortic arch, andheart outflow tract). Neural crest cells migrate in these regions during the 4th week of embryogenesis and constitute, along with paraxial mesoderm, the mesenchyme of these complex embryonic structures. Experiments of neural crest ablation on chick embryos and other animal models have shown that failure in migration/survival/differentiation of neural crest derived cells or imperfect epithelial–mesenchymal interaction in the development of pharyngeal arches, generate phenocopies of 22q11.2 deletion syndrome [Bockman et al., 1987; Frank et al., 2002; Hutson and Kirby, 2003]. Recent research found that genes mapping in the human DGA-critical region are expected to play an important function in controlling the development of neural crest derived cells or in their interaction with endodermal or mesodermal cells in the branchial arch system [Yamagishi, 2002]. In this report we describe a child who showed both 22q11.2 deletion syndrome features and two supernumerary tracheal bronchi. Bronchial branching anomalies are uncommon findings, mainly represented by supernumerary tracheal bronchus (STB) and displaced tracheal bronchus, whereas bridging bronchus, supernumerary esophageal bronchus and esophageal lung are more exceptional observations [Evans, 1990]. STB is defined as an adjunctive bronchus that originates from the tracheal lateral wall (segmentary), mostly on the right, or from the main bronchus (subsegmentary), and directs to the ipsilateral upper lobe territory [Ghaye et al., 2001]. A causal connection between 22q11.2 microdeletion and STB is plausible on the basis of the timing of embryo development. In fact the respiratory system

Sonic Hedgehog Is Essential for First Pharyngeal Arch Development

The secreted protein sonic hedgehog (Shh) is essential for normal development of many organs. Targeted disruption of Shh in mouse leads to near complete absence of craniofacial skeletal elements at birth, and mutation of SHH in human causes holoprosencephaly (HPE), frequently associated with defects of derivatives of pharyngeal arches. To investigate the role of Shh signaling in early pharyngeal arch development, we analyzed Shh mutant embryos using molecular markers and found that the first pharyngeal arch (PA1) was specifically hypoplastic and fused in the midline, and remaining arches were well formed at embryonic day (E) 9.5. Molecular analyses using specific markers suggested that the growth of the maxillary arch and proximal mandibular arch was severely defective in Shh-null PA1, whereas the distal mandibular arch was less affected. TUNEL assay revealed an increase in the number of apoptotic signals in PA1 of Shh mutant embryos. Ectodermal expression of fibroblast growth factor (Fgf)-8, a cell survival factor for pharyngeal arch mesenchyme, was down-regulated in the PA1 of Shh mutants. Consistent with this observation, downstream transcriptional targets of Fgf8 signaling in neural crest-derived mesenchyme, including Barx1, goosecoid, and Dlx2, were also down-regulated in Shh-null PA1. These results demonstrate that epithelial-mesenchymal signaling and transcriptional events coordinated by Shh, partly via Fgf8, is essential for cell survival and tissue outgrowth of the developing PA1.

Combined deficiencies ofMsx1andMsx2cause impaired patterning and survival of the cranial neural crest

The neural crest is a multipotent, migratory cell population that contributes to a variety of tissues and organs during vertebrate embryogenesis. Here, we focus on the function of Msx1 and Msx2, homeobox genes implicated in several disorders affecting craniofacial development in humans. We show that Msx1/2 mutants exhibit profound deficiencies in the development of structures derived from the cranial and cardiac neural crest. These include hypoplastic and mispatterned cranial ganglia, dysmorphogenesis of pharyngeal arch derivatives and abnormal organization of conotruncal structures in the developing heart. The expression of the neural crest markers Ap-2alpha, Sox10 and cadherin 6 (cdh6) in Msx1/2 mutants revealed an apparent retardation in the migration of subpopulations of preotic and postotic neural crest cells, and a disorganization of neural crest cells paralleling patterning defects in cranial nerves. In addition, normally distinct subpopulations of migrating crest underwent mixing. The expression of the hindbrain markers Krox20 and Epha4 was altered in Msx1/2 mutants, suggesting that defects in neural crest populations may result, in part, from defects in rhombomere identity. Msx1/2 mutants also exhibited increased Bmp4 expression in migratory cranial neural crest and pharyngeal arches. Finally, proliferation of neural crest-derived mesenchyme was unchanged, but the number of apoptotic cells was increased substantially in neural crest-derived cells that contribute to the cranial ganglia and the first pharyngeal arch. This increase in apoptosis may contribute to the mispatterning of the cranial ganglia and the hypoplasia of the first arch.

XTbx1 is a transcriptional activator involved in head and pharyngeal arch development in Xenopus laevis

The development of pharyngeal arch derivatives in mouse and zebrafish embryos depends on the activity of the transcription factor Tbx1. We cloned the Xenopus laevis orthologue of Tbx1 (XTbx1) and show that the pattern of expression is similar to that in other vertebrate species. Zygotic transcripts are first detected shortly after the mid-blastula transition and are localized to the presumptive mesoderm at mid-gastrula stages. XTbx1 expression persists in the lateral plate mesoderm at neurula stages and is found in the pharyngeal arches and otic vesicles from early tail bud stages onward. We demonstrate that XTbx1 is a transcriptional activator and that this trans-activation requires the C-terminal region of the protein. A dominant interfering mutant of XTbx1 disrupts the development of Xenopus head structures and pharyngeal arch derivatives. Lineage labeling reveals a requirement for XTbx1 function in cells that contribute to the pharyngeal mesoderm and for fgf8 expression.

Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors.

Birth defects, which occur in one out of 20 live births, often affect multiple organs that have common developmental origins. Human and mouse studies indicate that haploinsufficiency of the transcription factor TBX1 disrupts pharyngeal arch development, resulting in the cardiac and craniofacial features associated with microdeletion of 22q11 (del22q11), the most frequent human deletion syndrome. Here, we have generated an allelic series of Tbx1 deficiency that reveals a lower critical threshold for Tbx1 activity in the cardiac outflow tract compared with other pharyngeal arch derivatives, including the palatal bones. Mice hypomorphic for Tbx1 failed to activate expression of the forkhead transcription factor Foxa2 in the pharyngeal mesoderm, which contains cardiac outflow precursors derived from the anterior heart field. We identified a Fox-binding site upstream of Tbx1 that interacted with Foxa2 and was necessary for pharyngeal mesoderm expression of Tbx1, revealing an autoregulatory loop that may explain the increased cardiac sensitivity to Tbx1 dose. Downstream of Tbx1, we found a fibroblast growth factor 8 (Fgf8) enhancer that was dependent on Tbx1 in vivo for regulating expression in the cardiac outflow tract, but not in pharyngeal arches. Consistent with its role in regulating cardiac outflow tract cells Tbx1 gain of function resulted in expansion of the cardiac outflow tract segment derived from the anterior heart field as marked by Fgf10. These findings reveal a Tbx1-dependent transcriptional and signaling network in the cardiac outflow tract that renders mouse cardiovascular development more susceptible than craniofacial development to a reduction in Tbx1 dose, similar to humans with del22q11.

Effects of gestational exposure to ethane dimethanesulfonate in CD‐1 mice: Microtia and preliminary hearing tests

Microtia is a reduction in pinna size, usually seen in humans in conjunction with other medical conditions. We report microtia in CD-1 mice after gestational exposure to ethane dimethanesulfonate (EDS), an alkylating agent and adult rat Leydig cell toxicant. Time-pregnant CD-1 mice were administered 0, 80, or 160 mg EDS/kg on gestation days (GD) 11-17, or 0 or 160 mg EDS/kg on GD 11-13, GD 13-15 or GD 15-17. Pinnae were measured on postnatal days (PND) 4, 8, 18, and 28; and were observed for detachment from birth through PND 8. Branchial-arch derived skeletal structures and histology of the pinna was examined on PND 4 and 24. Brainstem auditory evoked response (BAER) tests were carried out at approximately PND 160 to determine possible effects on hearing. All offspring of EDS-treated dams exhibited bilateral, dose-related decreases in pinna size. Gestational exposure during GD 11-13 produced smaller ears than during GD 13-15 or 15-17, but not as small as the GD 11-17 regimen. Ossification of other pharyngeal arch derivatives was delayed whereas histology was unremarkable. BAER analysis showed a decrease in the proportion of adult offspring producing a quantifiable response to varied auditory stimuli among EDS-treated litters. Gestational exposure to EDS affects pinna development in the mouse, with a broad period of sensitivity during the second half of gestation. Microtia induced by EDS may be associated with hearing deficits, suggesting functional importance of pinna size or additional effects of EDS on ear development not detected by morphological examination.

Neural crest ablation does not alter pulmonary vein development in the chick embryo.

Cranial neural crest, which extends from the mid-diencephalon to somite five, plays an integral role in development of pharyngeal arch derivatives and supplies mesenchyme to the aortic arch arteries. Neural crest cells in pharyngeal arches three, four, and six migrate to the heart and are involved in aorticopulmonary and conotruncal septation. Ablation of the "cardiac" neural crest cells in chick embryos results in a variety of outflow tract anomalies, including persistent truncus arteriosus. Although other studies have shown the importance of the neural crest in the development of the cardiac outflow tract, the role of neural crest in venous development has not been established. This investigation evaluates the effect of cardiac neural crest ablation on the morphological development of the pulmonary vein. The presence of the pulmonary vein was confirmed initially at early stage 15 using histological sections and computer reconstructions of serially sectioned, normal embryos. India ink injections demonstrated a complete, patent pulmonary circuit at stage 18. Cardiac neural crest was ablated at stages 8-10. Operated, sham-operated, and control embryos were sacrificed at incubation day 11, and acrylic plastic casts prepared of the intravascular compartment. In experimental embryos with persistent truncus arteriosus, there were no morphological differences in the pulmonary veins, compared with shams and controls. These data indicate that the lesions of the cardiac neural crest have little morphological impact on pulmonary vein development. It is concluded that alterations in the cardiac neural crest are not involved in venous anomalies such as cor triatriatum and total or partial anomalous pulmonary venous return.