Yasumitsu Kodama

Genetic loci controlling susceptibility to γ-ray-induced thymic lymphoma

BALB/c is a susceptible strain for the development of γ-ray induced mouse thymic lymphoma whereas MSM shows resistance. Association analysis of 220 backcross mice between the two strains using 67 markers was carried out to identify loci involved in the control of susceptibility. The genotype of mice with lymphoma showed excess heterozygosity relative to MSM homozygosity at D2Mit15 and D4Mit12 and was skewed toward MSM-derived alleles at D5Mit5. The P values in Mantel-Cox test were 0.0048 (D2Mit15), 0.0034 (D4Mit12) and 0.0048 (D5Mit5), suggesting association at the three loci in the susceptibility. Cooperative effect on lymphomagenesis was also observed among the three loci. To obtain independent evidence for linkage at D4Mit12, we made partially congenic mice in which a D4Mit12 region in BALB/c was replaced by MSM-derived homolog. Examination for the lymphoma susceptibility in 78 progeny of the congenic mice confirmed the effect of the locus near D4Mit12 (P=0.0037). The result, together with the linkage analysis, shows that the locus near D4Mit12 is regarded as a confirmed linkage but the other two loci as marginally suggestive.

Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1 )

Genetic predisposition to cancers is significant to public health because a high proportion of cancers probably arise in a susceptible human subpopulation. Using a mouse model of γ-ray-induced thymic lymphomas, we performed linkage analysis and haplotype mapping that suggested Mtf-1, metal-responsive transcription factor-1 (Mtf-1), as a candidate lymphoma susceptibility gene. Sequence analysis revealed a polymorphism of Mtf-1 that alters the corresponding amino acid at position 424 in the proline-rich domain from a serine in susceptibility strains to proline in resistant strains. The transcriptional activity of Mtf-1 encoding serine and proline was compared by transfecting the DNA to Mtf-1-null cells, and the change to proline conferred a higher metal responsiveness in transfections. Furthermore, the resistant congenic strains possessing the Mtf-1 allele of proline type exhibited higher radiation inducibility of target genes than susceptible background strains having the Mtf-1 allele of serine type. Since products of the targets such as metallothionein are able to suppress cellular stresses generated by irradiation, these results suggest that highly inducible strains having Mtf-1 of proline type are refractory to radiation effects and hence are resistant to lymphoma development.

Ghost cell odontogenic carcinoma arising in the background of a benign calcifying cystic odontogenic tumor of the mandible

Ghost cell odontogenic carcinoma (GCOC) is a rare malignant variant of odontogenic tumor with ghost cells; only 29 cases are documented. Our patient was a 68-year-old man with a painless, well-defined, radiolucent swelling of the mandibular gingiva in the right incisor-to-molar region. It was diagnosed as a benign calcifying cystic odontogenic tumor (CCOT) on fenestration biopsy. Eighteen years later, he returned with swelling in the same area. The lesion was excised, diagnosed as GCOC, and considered a secondary malignant manifestation of the benign CCOT. No adjuvant chemotherapy or radiotherapy was administered, and his postoperative course was uneventful for 48 months, with no recurrence or distant metastasis. Among the 30 reported cases of GCOC, the mean age at diagnosis was 40.3 years, 22 (73%) involved the maxilla. Twelve (40%) were secondary malignant manifestations of benign CCOTs or dentinogenic ghost cell tumors. Five patients died of recurrence or distant metastasis.

The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ-ray-induced and N-methyl-N-nitrosourea-induced thymic lymphomas

Low‐penetrance genes control different susceptibilities to γ‐ray‐induced thymic lymphomas in mouse strains. Our previous genetic analyses with backcross mice between BALB/c and MSM strains and congenic lines localized one such gene near the D4Mit12 locus on chromosome 4. N‐Methyl‐N‐nitrosourea (MNU) is a guanine base‐alkylating agent and differs from γ‐radiation in its mechanism of mutagenic action. Accordingly, in this study, we examined whether or not the locus also provides susceptibility to MNU‐induced thymic lymphomas using 84 offsprings derived from congenic mice for D4Mit12. Association analysis provided a suggestive linkage at D4Mit12 (P=0.0075) and the linkage was sustained by the peak of likelihood ratio statistical values being at the same position as that for the γ‐ray‐induced lymphomas. The results strongly suggest that the BALB/c allele near D4Mit12 is associated with susceptibility to lymphomas induced by two carcinogenic agents having different mechanisms of mutagenic action.

Bcl11b transcription factor plays a role in the maintenance of the ameloblast-progenitors in mouse adult maxillary incisors

Rodent incisors maintain the ability to grow continuously and their labial dentin is covered with enamel. Bcl11b zinc-finger transcription factor is expressed in ameloblast progenitors in mouse incisors and its absence in Bcl11b(KO/KO) mice results in a defect in embryonic tooth development. However, the role of Bcl11b in incisor maintenance in adult tissue was not studied because of death at birth in Bcl11b(KO/KO) mice. Here, we examined compound heterozygous Bcl11b(S826G/KO) mice, one allele of which has an amino acid substitution of serine at position 826 for glycine, that exhibited hypoplastic maxillary incisors with lower concentrations of minerals at the enamel and the dentin, accompanying the maxillary bone hypoplasia. Histological examinations revealed hypoplasia of the labial cervical loop in incisors, shortening of the ameloblast progenitor region, and impairment in differentiation and proliferation of ameloblast-lineage cells. Interestingly, however, juvenile mice at 5days after birth did not show marked change in these phenotypes. These results suggest that attenuated Bcl11b activity impairs ameloblast progenitors and incisor maintenance. The number of BrdU label-retaining cells, putative stem cells, was lower in Bcl11b(S826G/KO) incisors, which suggests the incisor hypoplasia may be in part a result of the decreased number of stem cells. Interestingly, the level of Shh and FGF3 expressions, which are assumed to play key roles in the development and maintenance of ameloblasts and odontoblasts, was not decreased, though the expressed areas were more restricted in ameloblast progenitor and mesenchyme regions of Bcl11b(S826G/KO) incisors, respectively. Those data suggest that the incisor maintenance by Bcl11b is not directly related to the FGF epithelial-mesenchymal signaling loop including Shh but is intrinsic to ameloblast progenitors and possibly stem cells.

Spatio-temporal expression of Sox genes in murine palatogenesis

Members of the Sox gene family play critical roles in many biological processes including organogenesis. We carried out comparative in situ hybridisation analysis of seventeen Sox genes (Sox1-14, 17, 18 and 21) during murine palatogenesis from initiation to fusion of the palatal shelves above the dorsal side of the tongue. At palatal shelf initiation (E12.5), the localized expression of six Sox genes (Sox2, 5, 6, 9, 12 and 13) was observed in the shelves, whereas Sox4 and Sox11 showed ubiquitious expression. During the down-growth of palatal shelves (E13.5), Sox4, Sox5, and Sox9 exhibited restricted expression to the interior side of the palatal shelves facing the tongue. Following elevation of the palatal shelves (E14.5), Sox2, Sox11 and Sox21 expression was present in the midline epithelial seam. We thus identify dynamic spatio-temporal expression of Sox gene family during the process of palatogenesis.

Severe destruction of the temporomandibular joint with complete resorption of the condyle associated with synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome.

The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome consists of a combination of inflammatory bone disorders and dermatologic pathology. Bone lesions as a form of diffuse sclerosing osteomyelitis in the mandible occur in the posterior body and ramus. Bone lesions rarely spread to the temporomandibular joint (TMJ) where ankylosis may result. Herein we present an unusual case of SAPHO syndrome with TMJ involvement in which severe destruction of the TMJ occurred. We observed an extension of the invasive soft tissue lesion into the infratemporal fossa from the TMJ with complete resorption of the condyle. In contrast to other previously reported cases, in our case the condyle was strongly suspected as the primary site of the bone lesion with subsequent extension to the ramus and infratemporal fossa. The destructive nature and related symptoms resembled a malignant tumor.

Trp53 affects the developmental anomaly of clefts of the palate in irradiated mouse embryos but not clefts of the lip with or without the palate.

Abstract Narai, S., Kodama, Y., Maeda, Y., Yokoyama, M., Takagi, R. and Kominami, R. Trp53 Affects the Developmental Anomaly of Clefts of the Palate in Irradiated Mouse Embryos but not Clefts of the Lip with or without the Palate. Radiat. Res. 166, 877–882 (2006). Trp53-deficient mice exhibit increased incidences of developmental anomalies when irradiated, probably due to lack of Trp53-dependent apoptosis. A/J strain-derived CL/Fr mice develop clefts of the lip with or without the palate (CL/P) in approximately one-fifth of the embryos. We produced Trp53-deficient CL/Fr mice and examined the susceptibility to spontaneous development of CL/P and clefts of palate only (CPO), which differ in their developmental mechanisms, CL/P resulting from clefts of the primary palate and CPO from clefts of the secondary palate. The effect of radiation on the two phenotypes was also studied. Unexpectedly, no increase in the frequency of CL/P was observed under either condition, indicating that Trp53 deficiency does not contribute to genesis of CL/P. On the other hand, radiation enhanced the incidence of CPO in Trp53+/+ embryos but not in Trp53+/− and Trp53−/−/ embryos, suggesting that the absence or presence of only one allele of Trp53 is insufficient to hinder differentiation and proliferation of cells involved in the secondary palate formation. These results indicate that Trp53 function adversely affects the development of CPO when certain damaging agents such as radiation are given.

Placement of mandibular nerve block using computed tomography to locate the foramen ovale in a patient with severe dislocation after segmental mandiblectomy

Operations to the face and skull can obscure the landmarks that are required to locate the position of the foramen ovale. We describe the use of three-dimensional computed tomography (3D-CT) to guide the approach to the foramen ovale to block the mandibular nerve in a patient with a mandibular deformity that had been caused by segmental mandiblectomy. Successful blockage of the mandibular nerve controlled the pain, contributed to the relief of physical and mental stress, and avoided the side effects of analgesics and pain from inserting the blocking needle.

Alveolar Bone Grafting in Association With Polyostotic Fibrous Dysplasia and Bisphosphonate-Induced Abnormal Bone Turnover in a Bilateral Cleft Lip and Palate Patient: A Case Report

A case is presented of extensive alveolar bone grafting in a patient with bilateral cleft lip and palate and polyostotic fibrous dysplasia. The patient previously underwent bisphosphonate therapy. Because of an abnormal and often decreased bone turnover caused by the fibrous dysplasia and the bisphosphonate therapy, bone grafting in such a patient poses several potential difficulties. In addition, the histomorphometric analysis of the bone grafts showed markedly decreased bone turnover. However, alveolar bone grafting using the iliac crest was performed successfully. Sufficient occlusion was achieved by postoperative low-loading orthodontic treatment.