Research Spotlight

Xu, Q., Zhang, H., Wang, S., Qin, C. and Lu, Y. (2021). “Constitutive expression of spliced XBP1 causes perinatal lethality in mice.” Genesis: e23420.

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Upon endoplasmic reticulum (ER) stress, inositol-requiring enzyme 1 (IRE1) is activated and catalyzes nonconventional splicing of an unspliced X-box binding protein 1 (XBP1U) mRNA to yield a spliced XBP1 (XBP1S) mRNA that encodes a potent XBP1S transcription factor. XBP1S is a key mediator of the IRE1 branch that is essential for alleviating ER stress. We generated a novel mouse strain (referred to as “Xbp1(CS/+) ” mice) that constitutively expressed XBP1S after Cre recombinase-mediated recombination. Further breeding of these mice with Twist2 Cre recombinase (Twist2-Cre) knock-in mice generated Twist2-Cre;Xbp1(CS/+) mice. Most Twist2-Cre;Xbp1(CS/+) mice died shortly after birth. Reverse-transcription polymerase chain reaction (RT-PCR) showed that constitutive expression of XBP1S occurred in various mouse tissues examined, but not in the brain. Immunohistochemistry confirmed that although the immunostaining signals for total XBP1 (XBP1U and XBP1S) were found in the calvarial bones in both Twist2-Cre;Xbp1(CS/+) and control mice, the signals for XBP1S were only detected in the Twist2-Cre;Xbp1(CS/+) mice, but not in the control mice. These results suggest that a precise control of XBP1S production is essential for normal mouse development.

Roza, A., Sousa, E.M., Leite, A.A., Amaral-Silva, G.K., Morais, T.M.L., Wagner, V.P., Schuch, L.F., Vasconcelos, A.C.U., de Arruda, J.A.A., Mesquita, R.A., Fonseca, F.P., Abrahão, A.C., Agostini, M., de Andrade, B.A.B., da Silveira, E.J.D., Martínez-Flores, R., Rondanelli, B.M., Alberdi-Navarro, J., Robinson, L., Marin, C., Assunção Júnior, J.N.R., Valiati, R., Fregnani, E.R., Santos-Silva, A.R., Lopes, M.A., Hunter, K.D., Khurram, S.A., Speight, P.M., Mosqueda-Taylor, A., van Heerden, W.F.P., Carlos, R., Wright, J.M., de Almeida, O.P., Romañach, M.J. and Vargas, P.A. (2021). “Central odontogenic fibroma: an international multicentric study of 62 cases.” Oral Surg Oral Med Oral Pathol Oral Radiol 131(5): 549-557.

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OBJECTIVE: The aim of this study was to report the clinicopathologic features of 62 cases of central odontogenic fibroma (COdF). STUDY DESIGN: Clinical and radiographic data were collected from the records of 13 oral pathology laboratories. All cases were microscopically reviewed, considering the current World Health Organization classification of tumors and were classified according to histopathologic features. RESULTS: There were 43 females and 19 males (average age 33.9 years; range 8-63 years). Clinically, COdF lesions appeared as asymptomatic swellings, occurring similarly in the maxilla (n = 33) and the mandible (n = 29); 9 cases exhibited palatal depression. Imaging revealed well-defined, interradicular unilocular (n = 27), and multilocular (n = 12) radiolucencies, with displacement of contiguous teeth (55%) and root resorption (46.4%). Microscopically, classic features of epithelial-rich (n = 33), amyloid (n = 10), associated giant cell lesion (n = 7), ossifying (n = 6), epithelial-poor (n = 3), and granular cell (n = 3) variants were seen. Langerhans cells were highlighted by CD1a staining in 17 cases. Most patients underwent conservative surgical treatments, with 1 patient experiencing recurrence. CONCLUSIONS: To the best of our knowledge, this study represents the largest clinicopathologic study of COdF. Most cases appeared as locally aggressive lesions located in tooth-bearing areas in middle-aged women. Inactive-appearing odontogenic epithelium is usually observed within a fibrous/fibromyxoid stroma, occasionally exhibiting amyloid deposits, multinucleated giant cells, or granular cells.

Xie, X., Xu, C., Zhao, H., Wang, J. and Feng, J.Q. (2021). “A Biphasic Feature of Gli1(+)-Mesenchymal Progenitors during Cementogenesis That Is Positively Controlled by Wnt/β-Catenin Signaling.” J Dent Res: 220345211007429.

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Cementum, a specialized bony layer covering an entire molar root surface, anchors teeth into alveolar bone. Gli1, a key transcriptional activator in Hedgehog signaling, has been identified as a mesenchymal progenitor cell marker in various tissues, including the periodontal ligament (PDL). To address the mechanisms by which Gli1(+) progenitor cells contribute to cementogenesis, we used the Gli1(lacZ/+) knock-in line to mark Gli1(+) progenitors and the Gli1(CreERT2/+); R26R(tdTomato/+) line (named Gli1(Lin)) to trace Gli1 progeny cells during cementogenesis. Our data unexpectedly displayed a biphasic feature of Gli1(+) PDL progenitor cells and cementum growth: a negative relationship between Gli1(+) progenitor cell number and cementogenesis but a positive correlation between Gli1-derived acellular and cellular cementoblast cell number and cementum growth. DTA-ablation of Gli1(Lin) cells led to a cementum hypoplasia, including a significant reduction of both acellular and cellular cementoblast cells. Gain-of-function studies (by constitutive stabilization of β-catenin in Gli1(Lin) cells) revealed a cementum hyperplasia. A loss of function (by conditional deletion of β-catenin in Gli1(+) cells) resulted in a reduction of postnatal cementum growth. Together, our studies support a vital role of Gli1(+) progenitor cells in contribution to both types of cementum, in which canonical Wnt/β-catenin signaling positively regulates the differentiation of Gli1(+) progenitors to cementoblasts during cementogenesis.

Rios, J.J., Denton, K., Russell, J., Kozlitina, J., Ferreira, C.R., Lewanda, A.F., Mayfield, J.E., Moresco, E., Ludwig, S., Tang, M., Li, X., Lyon, S., Khanshour, A., Paria, N., Khalid, A., Li, Y., Xie, X., Feng, J.Q., Xu, Q., Lu, Y., Hammer, R.E., Wise, C.A. and Beutler, B. (2021). “Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice.” J Bone Miner Res Apr 9;S0022-3913(21)00087-1. [Epub ahead of print].

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Proper embryonic and postnatal skeletal development require coordination of myriad complex molecular mechanisms. Disruption of these processes, through genetic mutation, contributes to variation in skeletal development. We developed a high-throughput N-ethyl-N-nitrosourea (ENU)-induced saturation mutagenesis skeletal screening approach in mice to identify genes required for proper skeletal development. Here, we report initial results from live-animal X-ray and dual-energy X-ray absorptiometry (DXA) imaging of 27,607 G3 mice from 806 pedigrees, testing the effects of 32,198 coding/splicing mutations in 13,020 genes. A total of 39.7% of all autosomal genes were severely damaged or destroyed by mutations tested twice or more in the homozygous state. Results from our study demonstrate the feasibility of in vivo mutagenesis to identify mouse models of skeletal disease. Furthermore, our study demonstrates how ENU mutagenesis provides opportunities to create and characterize putative hypomorphic mutations in developmentally essential genes. Finally, we present a viable mouse model and case report of recessive skeletal disease caused by mutations in FAM20B. Results from this study, including engineered mouse models, are made publicly available via the online Mutagenetix database. © 2021 American Society for Bone and Mineral Research (ASBMR).

Zandinejad, A., Liang, H., Fisher Cosio, N.A. and Revilla-León, M. (2021). “Fabrication of a complete-arch implant-supported fixed interim prosthesis by using a cone beam computed tomography digital scan for a patient with primordial dwarfism: A dental technique.” J Prosthet Dent.

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A complete-arch implant-supported interim prosthesis was fabricated from a cone beam computed tomography digital scan of the implant abutments for a patient with primordial dwarfism. The patient presented with limited mouth opening, which hindered the use of a conventional impression technique. The described technique provided an alternative digital procedure to obtain a virtual implant definitive cast.