Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development.

Jaw morphogenesis is a complex event mediated by inductive signals that establish and maintain the distinct developmental domains required for formation of hinged jaws, the defining feature of gnathostomes. The mandibular portion of pharyngeal arch 1 is patterned dorsally by Jagged-Notch signaling and ventrally by endothelin receptor A (EDNRA) signaling. Loss of EDNRA signaling disrupts normal ventral gene expression, the result of which is homeotic transformation of the mandible into a maxilla-like structure. However, loss of Jagged-Notch signaling does not result in significant changes in maxillary development. Here we show in mouse that the transcription factor SIX1 regulates dorsal arch development not only by inducing dorsal Jag1 expression but also by inhibiting endothelin 1 (Edn1) expression in the pharyngeal endoderm of the dorsal arch, thus preventing dorsal EDNRA signaling. In the absence of SIX1, but not JAG1, aberrant EDNRA signaling in the dorsal domain results in partial duplication of the mandible. Together, our results illustrate that SIX1 is the central mediator of dorsal mandibular arch identity, thus ensuring separation of bone development between the upper and lower jaws.

Abnormal maxillary trapezoid pattern in human fetal cleft lip and palate.

OBJECTIVE: To elucidate abnormal growth patterns of human fetal maxillae with cleft lip and palate (CLP). SUBJECT: A total of 71 fetal maxillae with CLP were obtained from aborted human fetuses. METHOD: Dimensions of the maxillary trapezoid (MT), formed by the maxillary primary growth centers (MxPGC), were taken from radiographic images. The CLP dimensions were compared with maxillary trapezoid dimensions of normal fetuses from a previous study (Lee et al., 1992). MAIN OUTCOME MEASURES: Cleft lip subjects without a cleft palate, unilateral cleft lip-alveolar cleft or cleft palate (UCL+A/UCLP), and bilateral cleft lip-alveolar cleft or cleft palate (BCL+A/BCLP) displayed abnormal MT patterns. MT abnormalities were most marked in the BCL+A/BCLP cohort. RESULTS: The MT growth of prenatal CLP maxillae was severely arrested, resulting in abnormal MT shape on palatal radiograms. BCL+A/BCLP subjects had a more protruded nasal septum than subjects with other types of CLPs, while UCL+A/UCLP subjects showed severe deviation of the protruded nasal septum toward the noncleft side. Cleft lip-only subjects also exhibited abnormal MT growth. CONCLUSION: MT is primarily involved in CLPs, so that the MT shape could be utilized as a sensitive indicator for the analysis of maxillary malformation in different types of CLPs.

Embryological study of the development of the rat temporomandibular joint: highlighting the development of the glenoid fossa.

Basic embryological findings on the development of the temporomandibular joint have yet to be elucidated sufficiently. This experiment, was undertaken to find the standard time course of the development of the temporomandibular joint in rat fetuses. Serial frontal and sagittal sections of rat fetal heads (between 13.5 and 20.5 days post-conception [p.c.]) were examined microscopically. The condyle was recognized as a mesenchymal condensation at 14.5 days p.c., while the glenoid fossa was recognized at 15.5 days p.c. The mesenchymal condensation of the condyle had differentiated into chondrocytes by 16.5 days p.c., and endochondral ossification was recognized at 17.5 days p.c. The intramembranous ossification of the glenoid fossa was already recognized by 16.5 days p.c.; this started in the posterior region and progressed anteriorly between the zygomatic arch and the squamous part of the temporal bone. Ossification of the condyle had not been completed by 20.5 days p.c., a mass of hypertrophic chondrocytes remained in the center of the condylar head. The glenoid fossa was almost completely ossified by 19.5 days p.c. A coarse region of cells, reminiscent of apoptosis, was recognized in the region of the prospective superior joint space at 17.5 days p.c., and an actual joint space had formed by 18.5 days p.c. The inferior joint space was recognized at 19.5 days p.c. as a fissural cavity, but it was much narrower than its superior counterpart. The prospective meniscus was distinguished on the condylar surface at 17.5 days p.c. by the difference in the shape of its constituent cells. The results obtained here seem to be useful for further experiments and molecular biological studies.

Anatomic relationships of the orbital muscle of Müller in human fetuses.

A study was carried out in twenty human fetuses on the relationships of the orbital muscle of Müller. This muscle forms a lamina of smooth muscle fibres that cover the inferior orbital fissure. The latter is very wide during the fetal period because ossification of the bones that delimit this region is still incomplete. Some fibres of the orbital muscle extend along the superior orbital fissure under the inferior ophthalmic vein and the lower wall or floor of the cavernous sinus. This association suggests a possible influence on autonomically mediated vascular dynamics.

Mandibular growth rates in human fetal development.

A morphometric analysis of changing proportions in the developing mandible was undertaken in 18 human embryos and fetuses of both sexes (developmental age from 8 to 14 weeks, crown-rump length, CRL, from 34 to 110 mm), previously cleared and stained with a specific method for bone (alizarin red S). Reference points were located on the mandible, i.e. condylar process (Pcl), coronoid process (Pco), gnathion (GN), gonion (GO), superior symphyseal point (SSP), for measuring linear dimensions, i.e. Pcl-GN, Pcl-Pco, Pco-GN, GO-GN, SSP-GN. The gonial (Pcl-GO-GN) and the (Pcl-GN-Pcl) angles were also measured. All linear dimensions were correlated with the CRL by bivariate allometry (1n y = 1n a+b 1n x): they all grew with positive allometry, except GO-GN with isometry. The mandibular ramus grew relatively faster than the body, both in length and height, and the greatest growth rate was found for ramus height. The relation between mandibular shape and the craniofacial structures was investigated using scale drawings obtained from photographs of fetal skulls in lateral view. In the youngest fetuses the mandible was prognathic, then became retrognathic. During the period investigated the zygomatic process and squama of the temporal bone were in a lower and more inclined position in relation to the transverse plane passing through the zygomatic arch than in the newborn and adult. This study identifies parameters fitting changing trends in height, length and shape of the human mandible during the prenatal period (8-14 weeks); moreover, it emphasizes that the mandibular growth patterns differ significantly from those of successive development periods.

[Dermoid cyst in the fourth ventricle associated with Klippel-Feil syndrome].

Dermoid cysts in the central nervous system are often associated with various congenital disorders, especially dermal sinus and spina bifida. We report a case of dermoid cyst in the fourth ventricle associated with Klippel-Feil syndrome. A 47-year-old man with a long history of headache had been known to have a cystic lesion in the posterior fossa for 12 years. When he was referred to our hospital with complaints of transient tetraparesis, he showed bilateral cerebellar ataxia and minimal left hemiparesis. Furthermore, he was noted to have a webbed neck with a low hairline and facial asymmetry. CT and MRI showed multiple cerebral infarctions as well as a mass lesion in the posterior fossa. Cervical roentgenogram showed a fusion of C 2 and C 3 vertebrae. The tumor was totally removed via a suboccipital approach, and the diagnosis was a dermoid cyst. The present patient had not only dermoid cyst and Klippel-Feil syndrome but also hypertrophy of the zygomatic bone. The pathogenesis of the Klippel-Feil syndrome is presumed to be an intrauterine defect, with a failure of segmentation of mesodermal somites. The zygomatic bone is also derived from the mesoderm somites at early fourth week, too. From these points of view, the disturbance in the mesoderm before the fourth week of gestation might have played an important role in causing a dermoid cyst.

The phenotypic interdependence of the musculoskeletal characters of the mandibular arch in mice.

Evidence from studies of craniofacial anomalies and the evolutionary transition from reptiles to mammals suggests that the temporomandibular joint (TMJ), bony zygomatic arch, middle ear ossicles and mandibular muscle pattern may form a correlated suite of characters. To test the degree of phenotypic interdependence among these features, mandibular arch defects were analysed in prenatal mice. Retinoic palmitate was administered to pregnant mice on day 8.7 to produce test foetuses with malformations of the mandibular arch. A rating scale was developed for each of the four characters so that numerical values could be assigned to each phenotype encountered. Control animals were used to establish normal phenotypes for each character which were assigned a value of 1. Data from each test age, 16, 18 and 19 days postconception, were pooled and Spearmann rank correlation coefficients between each of the traits were calculated. Coefficients (R) range from a high of 0.87, between the TMJ and zygomatic arch, to a low of 0.67 between the zygomatic arch and the mandibular musculature showing highly significant correlations (P less than 0.0001) among all characters. Therefore, the data suggest that the musculoskeletal features of the mandibular arch are phenotypically interdependent during development.

Study of Os japonicum in Uttar Pradesh crania.

The incidence of Os japonicum has been studied in 500 Uttar Pradesh crania, and is found to be 4%. Typical bipartile zygomatic bone das present in 40 instances. In 6 bones only a horizontal groove was seen on the temporal surface. In one skull the zygomatic process of maxilla and the zygomatic process of the temporal bone were articulating directly on the temporal surface of the zygomatic bone. In another skull the maxilla and the temporal bone were articulating with each other along the lower border of the zygomatic bone, giving the appearance of a tripartile condition. The cause and significance of this trait is discussed in the light of available literature.