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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Cell cycle-related kinase is a crucial regulator for ciliogenesis and Hedgehog signaling in embryonic mouse lung development

  • Lee, Hankyu (College of Pharmacy, Dongguk University-Seoul) ;
  • Ko, Hyuk Wan (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
  • Received : 2019.11.28
  • Accepted : 2019.12.16
  • Published : 2020.07.31
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Abstract

Cell cycle-related kinase (CCRK) has a conserved role in ciliogenesis, and Ccrk defects in mice lead to developmental defects, including exencephaly, preaxial polydactyly, skeletal abnormalities, retinal degeneration, and polycystic kidney. Here, we found that Ccrk is highly expressed in mouse trachea and bronchioles. Ccrk mutants exhibited pulmonary hypoplasia and abnormal branching morphogenesis in respiratory organ development. Furthermore, we demonstrated that Ccrk mutant lungs exhibit not only impaired branching morphogenesis but also a significant sacculation deficiency in alveoli associated with reduced epithelial progenitor cell proliferation. In pseudoglandular stages, Ccrk mutant lungs showed a downregulation of Hedgehog (Hh) signaling and defects in cilia morphology and frequency during progenitor-cell proliferation. Interestingly, we observed that activation of the Hh signaling pathway by small-molecule smoothened agonist (SAG) partially rescued bud morphology during branch bifurcation in explants from Ccrk mutant lungs. Therefore, CCRK properly regulates respiratory airway architecture in part through Hh-signal transduction and ciliogenesis.

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References

  1. Morrisey EE and Hogan BL (2010) Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 18, 8-23 https://doi.org/10.1016/j.devcel.2009.12.010
  2. Herriges M and Morrisey EE (2014) Lung development: orchestrating the generation and regeneration of a complex organ. Development 141, 502-513 https://doi.org/10.1242/dev.098186
  3. Warburton D, Bellusci S, De Langhe S et al (2005) Molecular mechanisms of early lung specification and branching morphogenesis. Pediatr Res 57, 26R-37R https://doi.org/10.1203/01.pdr.0000159570.01327.ed
  4. Ingham PW and McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15, 3059-3087 https://doi.org/10.1101/gad.938601
  5. Kugler MC, Joyner AL, Loomis CA and Munger JS (2015) Sonic hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol 52, 1-13 https://doi.org/10.1165/rcmb.2014-0132TR
  6. Pepicelli CV, Lewis PM and McMahon AP (1998) Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr Biol 8, 1083-1086 https://doi.org/10.1016/S0960-9822(98)70446-4
  7. Li Y, Zhang H, Choi SC, Litingtung Y and Chiang C (2004) Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis. Dev Biol 270, 214-231 https://doi.org/10.1016/j.ydbio.2004.03.009
  8. Rutter M, Wang J, Huang Z, Kuliszewski M and Post M (2010) Gli2 influences proliferation in the developing lung through regulation of cyclin expression. Am J Respir Cell Mol Biol 42, 615-625 https://doi.org/10.1165/rcmb.2008-0390OC
  9. Ko HW (2012) The primary cilium as a multiple cellular signaling scaffold in development and disease. BMB Rep 45, 427-432 https://doi.org/10.5483/BMBRep.2012.45.8.167
  10. Reiter JF and Leroux MR (2017) Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol 18, 533-547 https://doi.org/10.1038/nrm.2017.60
  11. Jain R, Pan J, Driscoll JA et al (2010) Temporal relationship between primary and motile ciliogenesis in airway epithelial cells. Am J Respir Cell Mol Biol 43, 731-739 https://doi.org/10.1165/rcmb.2009-0328OC
  12. Snouffer A, Brown D, Lee H et al (2017) Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice. PLoS Genet 13, e1006912 https://doi.org/10.1371/journal.pgen.1006912
  13. Ko HW, Norman RX, Tran J, Fuller KP, Fukuda M and Eggenschwiler JT (2010) Broad-minded links cell cyclerelated kinase to cilia assembly and hedgehog signal transduction. Dev Cell 18, 237-247 https://doi.org/10.1016/j.devcel.2009.12.014
  14. Wang R, Xu XY, Zhu H et al (2019) Androgen Receptor Promotes Gastric Carcinogenesis via Upregulating Cell Cycle-Related Kinase Expression. J Cancer 10, 4178-4188 https://doi.org/10.7150/jca.34430
  15. Yang Y, Roine N and Makela TP (2013) CCRK depletion inhibits glioblastoma cell proliferation in a cilium-dependent manner. EMBO Rep 14, 741-747 https://doi.org/10.1038/embor.2013.80
  16. Weaver M, Yingling JM, Dunn NR, Bellusci S and Hogan BL (1999) Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. Development 126, 4005-4015 https://doi.org/10.1242/dev.126.18.4005
  17. Kunova Bosakova M, Nita A, Gregor T et al (2019) Fibroblast growth factor receptor influences primary cilium length through an interaction with intestinal cell kinase. Proc Natl Acad Sci U S A 116, 4316-4325 https://doi.org/10.1073/pnas.1800338116
  18. Moon H, Song J, Shin JO et al (2014) Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling. Proc Natl Acad Sci U S A 111, 8541-8546 https://doi.org/10.1073/pnas.1323161111
  19. Fernandes-Silva H, Correia-Pinto J and Moura RS (2017) Canonical Sonic Hedgehog Signaling in Early Lung Development. J Dev Biol 5, 3 https://doi.org/10.3390/jdb5010003