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Novel insights into a retinoic-acid-induced cleft palate based on Rac1 regulation of the fibronectin arrangement

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Abstract

Retinoic acid (RA)-induced cleft palate results from both extrinsic obstructions by the tongue and internal factors within the palatal shelves. Our previous study showed that the spatiotemporal expression of Rac1 regulates the fibronectin (FN) arrangement through cell density alterations that play an important role in palate development. In this study, we investigate the involvement of the Rac1 regulation of the FN arrangement in RA-induced cleft palate. Our results demonstrate that RA-induced intrinsic alterations in palatal shelves, including a delayed progress of cell condensation, delay palate development, even after the removal of the tongue. Further analysis shows that RA treatment diminishes the region-distinctive expression of Rac1 within the palatal shelves, which reversely alters the fibrillar arrangement of FN. Furthermore, RA treatment disrupts the formation of lamellipodia, which are indicative structures of cell migration that are regulated by Rac1. These results suggest that the Rac1 regulation of the FN arrangement is involved in RA-induced cleft palate through the regulation of cell migration, which delays the progress of cell condensation and subsequently influences the FN arrangement, inducing a delay in palate development. Our study provides new insights into the RA-induced impairment of palatal shelf elevation based on cell migration dynamics.

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References

  • Abbott BD, Pratt RM (1991) Retinoic acid alters epithelial differentiation during palatogenesis. J Craniofac Genet Dev Biol 11:315–325

    PubMed  CAS  Google Scholar 

  • Abbott BD, Harris MW, Birnbaum LS (1989) Etiology of retinoic acid-induced cleft palate varies with the embryonic stage. Teratology 40:533–553

    Article  PubMed  CAS  Google Scholar 

  • Almaidhan A, Cesario J, Landin Malt A, Zhao Y, Sharma N, Choi V, Jeong J (2014) Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation. BMC Dev Biol 14:3

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Brinkley LL, Bookstein FL (1986) Cell distribution during mouse secondary palate closure. II. Mesenchymal cells. J Embryol Exp Morphol 96:111–130

    PubMed  CAS  Google Scholar 

  • Chauhan BK, Lou M, Zheng Y, Lang RA (2011) Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia. Proc Natl Acad Sci U S A 108:18289–18294

    Article  PubMed Central  PubMed  Google Scholar 

  • Clagett-Dame M, Knutson D (2011) Vitamin A in reproduction and development. Nutrients 3:385–428

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cong W, Liu B, Liu S, Sun M, Liu H, Yang Y, Wang R, Xiao J (2014) Implications of the Wnt5a/CaMKII pathway in retinoic acid-induced myogenic tongue abnormalities of developing mice. Sci Rep 4:6082

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cuervo R, Valencia C, Chandraratna RA, Covarrubias L (2002) Programmed cell death is required for palate shelf fusion and is regulated by retinoic acid. Dev Biol 245:145–156

    Article  PubMed  CAS  Google Scholar 

  • Degitz SJ, Morris D, Foley GL, Francis BM (1998) Role of TGF-beta in RA-induced cleft palate in CD-1 mice. Teratology 58:197–204

    Article  PubMed  CAS  Google Scholar 

  • Ferguson MW (1988) Palate development. Development 103 (Suppl):41–60

    PubMed  Google Scholar 

  • Gritli-Linde A (2007) Molecular control of secondary palate development. Dev Biol 301:309–326

    Article  PubMed  CAS  Google Scholar 

  • Gritli-Linde A (2008) The etiopathogenesis of cleft lip and cleft palate: usefulness and caveats of mouse models. Curr Top Dev Biol 84:37–138

    Article  PubMed  CAS  Google Scholar 

  • He F, Popkie AP, Xiong W, Li L, Wang Y, Phiel CJ, Chen Y (2010) Gsk3beta is required in the epithelium for palatal elevation in mice. Dev Dyn 239:3235–3246

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Horie S, Yasuda M (2001) Alterations in palatal ruga patterns in Jcl:ICR mouse fetuses from dams treated with all-trans-retinoic acid. Hiroshima J Med Sci 50:17–25

    PubMed  CAS  Google Scholar 

  • Hu X, Gao J, Liao Y, Tang S, Lu F (2013) Retinoic acid alters the proliferation and survival of the epithelium and mesenchyme and suppresses Wnt/beta-catenin signaling in developing cleft palate. Cell Death Dis 4:e898

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ines FM, Valeria GG, Lis SM, Silvina NB, Matias SA, Maria VR (2014) Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor beta. J Cell Mol Med 18:1113–1123

    Article  CAS  Google Scholar 

  • Liang CC, Park AY, Guan JL (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2:329–333

    Article  PubMed  CAS  Google Scholar 

  • Okano J, Suzuki S, Shiota K (2007) Involvement of apoptotic cell death and cell cycle perturbation in retinoic acid-induced cleft palate in mice. Toxicol Appl Pharmacol 221:42–56

    Article  PubMed  CAS  Google Scholar 

  • Pratt RM, Goulding EH, Abbott BD (1987) Retinoic acid inhibits migration of cranial neural crest cells in the cultured mouse embryo. J Craniofac Genet Dev Biol 7:205–217

    PubMed  CAS  Google Scholar 

  • Sohn WJ, Yamamoto H, Shin HI, Ryoo ZY, Lee S, Bae YC, Jung HS, Kim JY (2011) Importance of region-specific epithelial rearrangements in mouse rugae development. Cell Tissue Res 344:271–277

    Article  PubMed  Google Scholar 

  • Suwa F, Jin Y, Lu H, Li X, Tipoe GL, Lau TY, Tamada Y, Kuroki K, Fang YR (2001) Alteration of apoptosis in cleft palate formation and ectomesenchymal stem cells influenced by retinoic acid. Okajimas Folia Anat Jpn 78:179–186

    Article  PubMed  CAS  Google Scholar 

  • Tang Q, Li L, Jin C, Lee JM, Jung HS (2015) Role of region-distinctive expression of Rac1 in regulating fibronectin arrangement during palatal shelf elevation. Cell Tissue Res (in press)

  • Tsunekawa N, Arata A, Obata K (2005) Development of spontaneous mouth/tongue movement and related neural activity, and their repression in fetal mice lacking glutamate decarboxylase 67. Eur J Neurosci 21:173–178

    Article  PubMed  Google Scholar 

  • Wang W, Kirsch T (2002) Retinoic acid stimulates annexin-mediated growth plate chondrocyte mineralization. J Cell Biol 157:1061–1069

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Xiao WL, Shi B, Huang L, Zheng Q, Li S, Lu Y (2006) Separation and culture of mouse embryonic palatal mesenchymal cells in vitro. Sichuan Da Xue Xue Bao Yi Xue Ban 37:137–140

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Division in Anatomy and Developmental Biology, Department of Oral Biology, Oral Science Research Center, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea

    Qinghuang Tang, Liwen Li, Min-Jung Lee, Qing Ge, Jong-Min Lee & Han-Sung Jung

  2. Oral Biosciences, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR, People’s Republic of China

    Han-Sung Jung

Authors
  1. Qinghuang Tang
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  2. Liwen Li
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  3. Min-Jung Lee
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  4. Qing Ge
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  5. Jong-Min Lee
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  6. Han-Sung Jung
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Corresponding authors

Correspondence to Jong-Min Lee or Han-Sung Jung.

Additional information

Qinghuang Tang and Liwen Li contributed equally as first authors.

Jong-Min Lee and Han-Sung Jung contributed equally as corresponding authors.

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3266). This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1817). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2014R1A2A1A11050764). This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIP) (No. 2012M3A9B4028738).

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Tang, Q., Li, L., Lee, MJ. et al. Novel insights into a retinoic-acid-induced cleft palate based on Rac1 regulation of the fibronectin arrangement. Cell Tissue Res 363, 713–722 (2016). https://doi.org/10.1007/s00441-015-2271-z

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  • DOI: https://doi.org/10.1007/s00441-015-2271-z

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