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REGULATION OF MURINE EMBRYONIC LUNG DEVELOPMENT BY NPAS1 AND NPAS3
Author(s) -
Zhou Shutang,
Shan Lin,
Sunday Mary E.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a208
Subject(s) - embryonic stem cell , lung , microbiology and biotechnology , biology , neuroscience , medicine , genetics , gene
Trachealess (TRL), a bHLH/PAS‐domain transcription factor, is the master regulator of Drosophila respiratory system development. The murine PAS‐domain proteins NPAS1 and NPAS3 have high amino acid sequence similarities to TRL. ARNT is the mammalian homolog of Drosophila TANGO, a functional herterodimer of TRL. We hypothesized that NPAS1 and/or NPAS3 are functional mammalian homologs of TRL with ARNT as a coactivator to regulate early lung formation. Quantitative RT‐PCR demonstrated that ARNT was expressed at a near‐constant level from E10.5 to P1, whereas NPAS1 and NPAS3 were abundant only at early stages. Knockdown of npas1, npas3 or Arnt gene expression with antisense oligodeoxynucleotides (AS‐ODN) or siRNA inhibited embryonic lung branching and altered lung morphogenesis both in vitro and in vivo. Previously, we observed that npas1‐AS treated lung buds have decreased mRNAs for multiple signaling pathways, including hedgehog and others. Addition of sonic hedgehog (Shh) protein completely rescue the branching defect due to npas1‐AS, including restoration of normal migration of myofibroblasts along the airways, while ephrinB1, angiopoietin‐2, and hyaluronic acid each partially rescued. In contrast, insulin‐like growth factor‐I had no effect. Our results indicate that NPAS1, NPAS3 and ARNT play a role in the regulation of embryonic lung development. Supported by NIH grant # RO1‐HL44984 (MES).