Temporal effects of Sprouty on lung morphogenesis

Dev Biol. 2003 Jun 1;258(1):154-68. doi: 10.1016/s0012-1606(03)00106-4.

Abstract

Paracrine signaling mediated by FGF-10 and the FGF-R2IIIb receptor is required for formation of the lung. To determine the temporal requirements for FGF signaling during pulmonary morphogenesis, Sprouty-4 (Spry-4), an intracellular FGF receptor antagonist, was expressed in epithelial cells of the fetal lung under control of a doxycycline-inducible system. Severe defects in lobulation and severe lung hypoplasia were observed when Spry-4 was expressed throughout fetal lung development (E6.5-E18.5) or from E6.5 until E13.5. Effects of Spry-4 on branching were substantially reversed by removal of doxycycline from the dam at E12.5, but not at E13.5. In contrast, when initiated late in development (E12.5 to birth), Spry-4 caused less severe pulmonary hypoplasia. Expression of Spry-4 from E16.5 to E18.5 reduced lung growth and resulted in perinatal death due to respiratory failure. Expression of Spry-4 during the saccular and alveolar stages, from E18.5 to postnatal day 21, caused mild emphysema. These findings demonstrate that the embryonic-pseudoglandular stage is a critical time period during which Spry-sensitive pathways are required for branching morphogenesis, lobulation, and formation of the peripheral lung parenchyma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation
  • Doxycycline / pharmacology
  • Female
  • Fibroblast Growth Factor 10
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Profiling
  • Lung / blood supply
  • Lung / drug effects
  • Lung / embryology*
  • Mice
  • Mice, Transgenic
  • Morphogenesis / drug effects
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / pharmacology*
  • Organ Culture Techniques
  • Pregnancy
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Repressor Proteins / genetics*
  • Signal Transduction
  • Time Factors

Substances

  • Fgf10 protein, mouse
  • Fibroblast Growth Factor 10
  • Nerve Tissue Proteins
  • Receptors, Fibroblast Growth Factor
  • Repressor Proteins
  • Spry4 protein, mouse
  • Fibroblast Growth Factors
  • Doxycycline