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Yasuo Sakai 1 , M.D., Ph.D. Junko Okano 2 , M.D., Ph.D. Kohei Shiota 3 , M.D., Ph.D.

Retinoic Acid Induces Cleft Palate by Suppressing Fgf10 in the Bend Region of the Palatal Shelves. Yasuo Sakai 1 , M.D., Ph.D. Junko Okano 2 , M.D., Ph.D. Kohei Shiota 3 , M.D., Ph.D. Institutes 1 Department of Plastic Surgery, Osaka University School of Medicine, Japan

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Yasuo Sakai 1 , M.D., Ph.D. Junko Okano 2 , M.D., Ph.D. Kohei Shiota 3 , M.D., Ph.D.

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  1. Retinoic Acid Induces Cleft Palate by Suppressing Fgf10 in the Bend Region of the Palatal Shelves. Yasuo Sakai1, M.D., Ph.D. Junko Okano2 , M.D., Ph.D. Kohei Shiota3 , M.D., Ph.D.

  2. Institutes 1Department of Plastic Surgery, Osaka University School of Medicine, Japan 2Developmental Skin Biology Section, NIAMS, National Institutes of Health, USA 3Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Japan Disclosure/Financial Support Supported in part by Grant-in-Aid Scientific Research (C) (19590181) from the Ministry of Education, Culture, Sports, Science and Technology (to Y.S.).

  3. Objective of the Study Retinoic acid (RA) is essential for normal embryonic development in vertebrates. We have examined the affect of RA on the palate formation. In the study, we focused on the bend region of the palatal shelves where is critical for their elevation.

  4. Palate Development T, tongue; P, palatal shelf. E11.5-13.5: Elongation P T E14.5: Elevation Bend Region E15.0: Fusion

  5. Materials and Methods • Cyp26b1 knock out (KO) mice • RA treatment • Gastric intubation to E11.5 pregnant ICR mice (RA100mg/kg) • In situ hybridization • RARE (RA response element)-hsp lacZ transgenic mice • Real-time RT-PCR

  6. Results-1 Both Cyp26b1 (RA-degrading enzyme) KO embryos and RA-treated ones revealed cleft palate without elevation of the palatal shelves. Wild type Cyp26b1-/- P P T T E15.5 gg T, tongue; P, palatal shelf; gg, genioglossus muscle. Note abnormal protrusions on the tongue (arrows) and poorly differentiated muscles (arrow heads) in the mutant.

  7. Results-2 Expression patterns ofCyp26b1 in the developing palate. Wild type RA-treated E11.5 E13.5 P P T T P P T T T, tongue; P, palatal shelf. Note Cyp26b1 is temporally expressed in the future bend region (arrow) at E11.5.

  8. Results-3 Expression patterns ofRaldh2 (RA-metabolizing enzyme) and RARE-laZ in the developing palate. Wild type Cyp26b1-/- RA-treated V2 V2 P P V2 Raldh2 E11.0 RARE-lacZ E13.5 P T T T P P P T T T T, tongue; P, palatal shelf; V2, cranial nerve V2.

  9. Results-4 Fgf10 in the bend region is down-regulated both in Cyp26b1-/- embryos and RA-treated ones. Wild type Cyp26b1-/- RA-treated E11.5 E13.5 P P P T T T P P T P T T sg T, tongue; P, palatal shelf; sg, submandibular gland. Altered expression patterns of Fgf10in the bend region (arrows).

  10. Results-5 Real-time PCR after RA treatment shows Fgf10 in the palatal shelves is significantly down-regulated at E11.5 (*P<0.01) and at E12.5 (*P<0.05). Control RA-treated

  11. Results-6 Expressionpatterns of cleft palate related genes, Bmp2 and Shh at E13.5. Wild type Cyp26b1-/- RA-treated P Bmp2 Shh P T P T T P P P T T T T, tongue; P, palatal shelf.

  12. Conclusions

  13. Significance of the Findings Fgf10 is one of target genes of Tbx1, a candidate gene of DiGeorge/velocardiofacial syndrome (DGS/VCFS). Tbx1 can induce expressions of Cyp26s and is also down-regulated in response to excess RA. Our findings provide a new insight into the important role of the bend region for the elevation of palatal shelves and the pathogenetic and molecular mechanisms of cleft palate caused by excess RA.

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