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ENU LARGE-SCALE MUTAGENESIS AND QUANTITATIVE TRAIT LINKAGE (QTL) ANALYSIS IN MICE: NOVEL TECHNOLOGIES FOR SEARCHING POLYGENETIC DETERMINANTS OF CRANIOFACIAL ABNORMALITIES

¹ The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, Biomaterials and Hospital Dentistry, UCLA School of Dentistry, Box 951668, CHS B3-087, Los Angeles, CA 90095; ² Department of Pathology and Laboratory Medicine, ³ Department of Medicine, and ⁴ Department of Microbiology and Molecular Genetics, UCLA, Los Angeles, CA; ⁵ Department of Orthopedic Surgery, UCLA School of Medicine, Los Angeles, CA; ⁶ Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH;

View larger version (56K): [in a new window]   Figure 1. Submental-vertex cephalographs of C57BL/6J (A) and DBA/2J mice (B). The zygomatic arch width was measured between points Zb and Zc (horizontal arrow), and the snout length was measured between points I and Za (vertical arrow). (C) Distribution of the zygomatic arch width measurements (Zb-Zc) of F2 mice. Each blue square represents a measurement from an F2 mouse. The average Zb-Zc measurements of C57BL/6J (red line) and DBA/2J (yellow line) are 2.60 (SD ± 0.18) mm and 3.16 (SD ± 0.10) mm, respectively. The differences between the average measurements of C57BL/6J and DBA/2J mice are statistically significant (p = 0.0102). (D) One hundred and ten F2 mice were subjected to the cephalometric analysis and the whole-genome microsatellite QTL analysis.

View larger version (34K): [in a new window]   Figure 2. Radiographs of ENU mutants exhibiting craniofacial abnormalities. (A) Stubby, an ENU mutant exhibiting Angle’s class III malocclusion, and incisors come into contact at the edge-to-edge position. (B) Mastodon displays underbite, resulting in the continuous growth of both maxillary and mandibular incisors with no compensatory occlusal wear. The long mandibular incisors protrude, and the long maxillary incisors curl back to form complete circles.

View larger version (49K): [in a new window]   Figure 3. Standardized cephalostat-assisted radiographs of wild-type mice. (A) Lateral cephalograph. (B) Submental-vertex cephalograph. Description of the measurement points is listed in the Table.

View larger version (97K): [in a new window]   Figure 4. Lateral and submental-vertex cephalographs of the ENU mutant, Stubby (A and C, respectively), and the wild-type control (B and D, respectively). (E) The cephalometric measurements depicted the underdevelopment of the frontal components of the maxilla and mandible in Stubby.

View larger version (47K): [in a new window]   Figure 5. 3D cephalometric measurements on microCT images of C57BL/6J and DBA/2J mice. The length and size measurements of the mandible for the right side (r) and left side (l) showed good agreement, suggesting the minimal error from the image acquisition process.