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Biomedical subjects

Martyn T Cobourne

Publications and source records attributed to Martyn T Cobourne.

14 recordsLinked to original sources
PubMed2007

Abnormal hair development and apparent follicular transformation to mammary gland in the absence of hedgehog signaling.

We show that removing the Shh signal tranducer Smoothened from skin epithelium secondarily results in excess Shh levels in the mesenchyme. Moreover, the phenotypes we observe reflect decreased epithelial Shh signaling, yet increased mesenchymal Shh signaling. For example, the latter contributes to exuberant hair follicle (HF) induction, while the former depletes the resulting follicular stem cell niches. This disruption of the niche apparently also allows the remaining stem cells to initiate hair formation at inappropriate times. Thus, the temporal structure of the hair cycle may depend on the physical structure of the niche. Finally, we find that the ablation of epithelial Shh signaling results in unexpected transformations: the follicular outer root sheath takes on an epidermal character, and certain HFs disappear altogether, having adopted a strikingly mammary gland-like fate. Overall, our study uncovers a multifaceted function for Shh in sculpting and maintaining the integrity and identity of the developing HF.

Animals↗
PubMed2006

Sonic hedgehog in the pharyngeal endoderm controls arch pattern via regulation of Fgf8 in head ectoderm.

Fgf8 signalling is known to play an important role during patterning of the first pharyngeal arch, setting up the oral region of the head and then defining the rostral and proximal domains of the arch. The mechanisms that regulate the restricted expression of Fgf8 in the ectoderm of the developing first arch, however, are not well understood. It has become apparent that pharyngeal endoderm plays an important role in regulating craniofacial morphogenesis. Endoderm ablation in the developing chick embryo results in a loss of Fgf8 expression in presumptive first pharyngeal arch ectoderm. Shh is locally expressed in pharyngeal endoderm, adjacent to the Fgf8-expressing ectoderm, and is thus a candidate signal regulating ectodermal Fgf8 expression. We show that in cultured explants of presumptive first pharyngeal arch, loss of Shh signalling results in loss of Fgf8 expression, both at early stages before formation of the first arch, and during arch formation. Moreover, following removal of the endoderm, Shh protein can replace this tissue and restore Fgf8 expression. Overexpression of Shh in the non-oral ectoderm leads to an expansion of Fgf8, affecting the rostral-caudal axis of the developing first arch, and resulting in the formation of ectopic cartilage. Shh from the pharyngeal endoderm thus regulates Fgf8 in the ectoderm and the role of the endoderm in pharyngeal arch patterning may thus be indirectly mediated by the ectoderm.

Animals↗
PubMed2006

The clinical features and aetiological basis of primary eruption failure.

Primary failure of eruption (PFE) is a poorly understood condition associated with tooth eruption failure. This investigation systematically reviews the literature, evaluates clinical features and associations with PFE, and describes five further cases. Publications were selected and identified as describing PFE when there was no identifiable aetiological factor contributing to eruption failure and no evidence of successful orthodontic extrusion of the affected tooth or teeth. A data abstraction form recorded the following additional information; subject age, gender, general health status, and teeth present. Eighteen publications were sourced that detailed at least one case of PFE in a manner conforming to the selection criteria; these papers included a total of 35 individual cases, to which five previously unreported subjects were added. Within the whole sample of 40 cases, a total of 24 (60 per cent) were females and 16 (40 per cent) males. First and second molar teeth were most commonly affected; incisors, canines, and premolars were also involved, but with a reduced individual frequency. There was no significant difference in incidence between the maxilla and mandible, or between left and right sides. A family history of eruption failure was found in almost 50 per cent of the sample, with eruption failure or ankylosis affecting at least one primary tooth, also a common finding. Within the 40 cases, hypodontia was present at levels higher than population norms. PFE appears to be a condition that predominantly affects the molar dentition. The increased frequency of hypodontia in affected individuals and common findings of a family history regarding tooth eruption problems suggests a significant genetic component to the aetiology of this rare condition.

Adolescent↗
PubMed2006

Hedgehog pathway gene expression during early development of the molar tooth root in the mouse.

Sonic hedgehog is a secreted protein important for many aspects of embryonic development. In the developing tooth, Shh expression is restricted to the epithelial compartment and plays an important role during both initiation and subsequent coronal morphogenesis. We have investigated the expression of Shh and constituent members of the signalling pathway during early development of the molar tooth root in the mouse and find the presence of transcripts in Hertwig's epithelial root sheath. These epithelial cells of the root sheath and the surrounding apical mesenchyme of the dental papilla and follicle also expressed the Shh receptor Ptc1, agonist Smo and Gli downstream transcriptional effectors; however, this response occurred over short range. In contrast, the Shh antagonists Hip1 and Gas1 were both expressed at a distance from these responding cells, in more peripheral regions of the developing root. Transcripts of the Skn acyl transferase lacked specific expression in early root structures.

Animals↗
PubMed2006

Neural crest cells and patterning of the mammalian dentition.

The mammalian dentition is composed of serial groups of teeth, each with a distinctive crown and root morphology, highly adapted to its particular masticatory function. In the embryo, generation of individual teeth within the jaws relies upon interactions between ectoderm of the first branchial arch and the neural crest-derived ectomesenchymal cells that migrate into this region from their site of origin along the neural axis. Classic tissue recombination experiments have provided evidence of an essential role of the ectoderm in initiating tooth development; however, the underlying ectomesenchyme rapidly acquires dominance in establishing shape. A key question is how these cells acquire this positional information. One theory suggests that ectomesenchymal cells are pre-patterned with respect to shape generation. Alternatively, this cell population acquires positional information within the first branchial arch itself, following migration. Recent molecular evidence suggests a high degree of plasticity within these ectomesenchymal cells. In particular, signalling molecules within the ectoderm exert a time-dependent influence upon the ectomesenchyme by establishing specific domains of homeobox gene expression. Initially, these ectomesenchymal cells are plastic and able to respond to signalling from the ectoderm, however, this plasticity is rapidly lost and pattern information becomes fixed. Therefore, in the first branchial arch, local regulation between the ectoderm and neural crest-derived ectomesenchyme is crucial in establishing the appropriate tooth shape in the correct region of the jaw.

Animals↗
PubMed2006

Tooth development: 1. Generating teeth in the embryo.

Teeth are organs that develop in the embryo via a series of interactions between oral epithelium and neural crest-derived ectomesenchyme of the early jaws. These interactions are initiated by the regional production of signalling molecules in the oral epithelium and the transfer of information to the underlying mesenchyme via homeobox gene transcription. This article describes how these interactions are co-ordinated in the embryo during development of the dentition and provides a theoretical basis for the second article in this series; understanding how biologists are attempting to generate teeth artificially in the laboratory.

Animals↗
PubMed2006

Tbx1 is expressed at multiple sites of epithelial-mesenchymal interaction during early development of the facial complex.

TBX1 encodes a T-box-containing transcription factor, which is thought to be a key player in the aetiology of the DiGeorge and Velocardiofacial syndromes (DGS/VCFS). In addition to defects affecting structures derived from the pharyngeal pouches, these patients exhibit varying degrees of facial dysmorphology and cleft palate. We have analysed the expression of murine Tbx1 during early facial development and found transcripts at sites of known epithelial-mesenchymal interaction. In particular, Tbx1 was expressed in epithelium of the early facial processes, including the fronto-nasal, medial and lateral nasal and palatine. Transcripts were also localised to the epithelium of developing tooth germs and hair follicles at several stages during their early development. Together, these expression domains suggest a role for Tbx1 in mediating epithelial-mesenchymal signalling in regions of the developing face, a finding which is consistent with the spectrum of facial deformity encountered amongst subjects affected by DGS/VCFS.

Animals↗
PubMed2005

Dental transposition as a disorder of genetic origin.

A sample of 85 dental transpositions in 75 subjects (27 male, 48 female; mean age at diagnosis 12.25 years) involving both maxillary and mandibular arches was analysed using dental panoramic radiographs and clinical records. Transposition affected the maxillary dentition (76 per cent) more frequently than the mandibular dentition (24 per cent). Unilateral transposition accounted for 88 per cent of cases, with the maxilla being involved more commonly than the mandible. Overall, the most common transposition involved the maxillary canine and first premolar (58 per cent). Considering the jaws in isolation, the canine and first premolar were the most commonly affected teeth in the maxilla (83 per cent) whilst in the mandible, the canine and lateral incisor teeth were most commonly transposed (73 per cent). No significant difference in symmetrical distribution of the unilateral transposition sample occurred. There was evidence of associated hypodontia in 41 per cent of the sample; however, if third molars were excluded, this figure decreased to 25 per cent. Peg-shaped maxillary lateral incisors were judged to be present in 27 per cent of subjects, whilst 41 per cent had retained primary teeth; all of these, except one, were primary canines. Overall, the majority of the sample (76 per cent) demonstrated at least one of the dental anomalies under investigation. Multivariate analysis showed associations between unilateral transposition, gender, and the presence of peg-shaped maxillary lateral incisors; whilst bilateral transposition was more closely associated with gender and the presence of retained primary teeth. There was a poor association between both unilateral and bilateral transposition and hypodontia. Together, these results suggest a mutifactorial aetiology to this disorder, with both genetic and environmental factors playing an important role.

Adolescent↗
PubMed2005

Expression of the Hedgehog antagonists Rab23 and Slimb/betaTrCP during mouse tooth development.

The sonic hedgehog signalling peptide has been demonstrated to play an important role in the growth and patterning of several organs including the tooth. Inappropriate activation of Shh signalling in the embryo causes various patterning defects and complex regulation of this pathway is important during normal development. A growing list of diverse antagonists have been identified that restrict Shh signalling in the embryo, however, only Ptc1, Gas1 and Hip1 have been studied during tooth development. We have examined the expression pattern of the putative antagonists Rab23 and Slimb/betaTrCP during early murine odontogenesis and find that these molecules are expressed in the developing tooth. Interestingly, Rab23 demonstrates contrasting expression domains in the incisor and molar dentition during the cap stage, being restricted to the mesenchymal compartment of molar teeth and the epithelium of the enamel knot in incisor teeth. These findings provide the first evidence of distinct regulatory pathways for Shh in teeth of different classes.

Animals↗
PubMed2004

Restriction of sonic hedgehog signalling during early tooth development.

The signalling peptide encoded by the sonic hedgehog gene is restricted to localised thickenings of oral epithelium, which mark the first morphological evidence of tooth development, and is known to play a crucial role during the initiation of odontogenesis. We show that at these stages in the murine mandibular arch in the absence of epithelium, the Shh targets Ptc1 and Gli1 are upregulated in diastema mesenchyme, an edentulous region between the sites of molar and incisor tooth formation. This ectopic expression is not associated with Shh transcription but with Shh protein, undetectable in the presence of epithelium. These findings suggest that, in diastema mesenchyme, restriction of Shh activity is dependent upon the overlying epithelium. This inhibitory activity was demonstrated by the ability of transplanted diastema epithelium to downregulate Ptc1 in tooth explants, and for isolated diastema mesenchyme to express Ptc1. A candidate inhibitor in diastema mesenchyme is the glycosylphosphatidylinositol-linked membrane glycoprotein Gas1. Gas1 is normally expressed throughout mandibular arch mesenchyme; however, in the absence of epithelium this expression was downregulated specifically in the diastema where ectopic Shh protein was identified. Although Shh signalling has no effect upon Gas1 expression in mandibular arch mesenchyme, overexpression of Gas1 results in downregulation of ectopic Ptc1. Therefore, control of the position of tooth initiation in the mandibular arch involves a combination of Shh signalling at sites where teeth are required and antagonism in regions destined to remain edentulous.

Animals↗
PubMed2004

The complex genetics of cleft lip and palate.

Clefts of the lip and palate are a common craniofacial anomaly, requiring complex multidisciplinary treatment and having lifelong implications for affected individuals. The aetiology of both cleft lip with or without cleft palate (CLP) and isolated cleft palate (CP) is thought to be multifactorial, with both genetic and environmental factors playing a role. In recent years, a number of significant breakthroughs have occurred with respect to the genetics of these conditions, in particular, characterization of the underlying gene defects associated with several important clefting syndromes. These include the identification of mutations in the interferon regulatory factor-6 (IRF6) gene as the cause of van der Woude syndrome and the poliovirus receptor related-1 (PVRL1) gene as being responsible for an autosomal recessive ectodermal dysplasia syndrome associated with clefting. While no specific disease-causing gene mutations have been identified in non-syndromic clefting, a number of candidate genes have been isolated through both linkage and association studies. However, it is clear that environmental factors also play a role and an important area of future research will be to unravel interactions that occur between candidate genes and environmental factors during early development of the embryo. Orthodontists are intimately involved in the therapeutic management of individuals affected by CLP and it is important that they keep abreast of current knowledge of the aetiology behind these conditions. This review aims to summarize some of the more significant advances in the genetics of CLP and highlight current thinking on the modes of inheritance and genetic loci that might be involved in this complex disorder.

Cleft Lip↗
PubMed2003

Tooth and jaw: molecular mechanisms of patterning in the first branchial arch.

The mammalian jaw apparatus is ultimately derived from the first branchial arch derivatives, the maxillary and mandibular processes, and composed of a highly specialised group of structures. Principle amongst these are the skeletal components of the mandible and maxilla and the teeth of the mature dentition. Integral to the development of these structures are signalling interactions between the stomodeal ectoderm and underlying neural crest-derived ectomesenchymal cells that populate this region. Recent evidence suggests that in the early mouse embryo, regionally restricted expression of homeobox-containing genes, such as members of the Dlx, Lhx and Gsc classes, are responsible for generating early polarity in the first branchial arch and establishing the molecular foundations for patterning of the skeletal elements. Teeth also develop on the first branchial arch and are derived from both ectoderm and the underlying ectomesenchyme. Reciprocal signalling interactions between these cell populations also control the odontogenic developmental programme, from early patterning of the future dental axis to the initiation of tooth development at specific sites within the ectoderm. In particular, members of the Fibroblast growth factor (Fgf), Bmp, Hedgehog and Wnt families of signalling molecules induce regionally restricted expression of downstream target genes in the odontogenic ectomesenchyme. Finally, the processes of morphogenesis and cellular differentiation ultimately generate a tooth of specific class. Many of the same genetic interactions that are involved in early tooth development mediate these effects through the activity of localised signalling centres within the developing tooth germ.

Animals↗
PubMed2002

Expression and regulation of hedgehog-interacting protein during early tooth development.

Sonic hedgehog (Shh) expression is highly localized to the epithelium at the future sites of tooth development. This restricted expression suggests that inhibition of Shh in areas where teeth do not form may be an important mechanism in tooth germ localization. Recently, Hip, a putative vertebrate antagonist of Shh, has been identified. We have investigated the expression of Hip during early tooth development and found it not to be localized in cells immediately adjacent to Shh-expressing cells, but rather at a distance, separated by cells expressing Ptc1. Hip is also regulated by Shh in the first branchial arch. Shh-soaked agarose beads are able to induce the expression of Hip in odontogenic mesenchyme. A role for Hip might be to prevent the spread of excess Shh ligand beyond an immediate Ptc1-induced zone in odontogenic mesenchyme. This mechanism would therefore restrict Shh signaling specifically to those regions along the oral axis that are destined to form teeth.

Animals↗