Timeless in lung morphogenesis

Authors

  • Jing Xiao,

    1. Department of Pediatrics, Women's & Children's Hospital & Department of Medicine, Will Rogers Institute Pulmonary Research Center, School of Medicine, University of Southern California, Los Angeles, California
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  • Changgong Li,

    1. Department of Pediatrics, Women's & Children's Hospital & Department of Medicine, Will Rogers Institute Pulmonary Research Center, School of Medicine, University of Southern California, Los Angeles, California
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  • Nian-Ling Zhu,

    1. Department of Pediatrics, Women's & Children's Hospital & Department of Medicine, Will Rogers Institute Pulmonary Research Center, School of Medicine, University of Southern California, Los Angeles, California
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  • Zea Borok,

    1. Department of Pediatrics, Women's & Children's Hospital & Department of Medicine, Will Rogers Institute Pulmonary Research Center, School of Medicine, University of Southern California, Los Angeles, California
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  • Parviz Minoo

    Corresponding author
    1. Department of Pediatrics, Women's & Children's Hospital & Department of Medicine, Will Rogers Institute Pulmonary Research Center, School of Medicine, University of Southern California, Los Angeles, California
    • Women's & Children's Hospital, LAC+USC Medical Center, 1801 E. Marengo Street, Room 1G1, Los Angeles, CA 90033
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Abstract

The Clock gene, timeless, regulates circadian rhythm in Drosophila, but its vertebrate homolog is critical to embryonic development. Timeless was shown to be involved in murine urethral bud branching morphogenesis. We generated a polyclonal antibody to mouse TIMELESS (mTIM) and studied its distribution and its potential role during lung development, which also requires branching morphogenesis. In the early mouse embryo, TIM was localized to all organs, especially the neural epithelium. In embryonic day (E) 9.5 embryos, TIM was present in both epithelial and mesenchymal cells at the onset of lung morphogenesis. In E15 embryos, TIM decreased in the mesenchyme but remained pronounced in the epithelium of both large and small airways. Later, TIM was localized to a specific subset of epithelial cells with alveolar type 2 phenotype. This finding was verified by immunostaining of isolated alveolar type 2 cells. In the proximal airways, TIM was colocalized with CCSP to nonciliated columnar epithelial cells. Antisense oligonucleotides to mTim specifically inhibited branching morphogenesis of embryonic lungs in explant culture without affecting SpC expression an alveolar type 2 cell marker. In cultured lung cells, expression of TIM is independent of cell cycle and proliferation. These studies indicate that the function of Timeless is highly conserved in organs whose formation requires branching morphogenesis. Developmental Dynamics 228:82–94, 2003. © 2003 Wiley-Liss, Inc.

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