Related Experiment Videos
An allelic series at the PDGFalphaR locus indicates unequal contributions of distinct signaling pathways during
Richard A Klinghoffer1, T Guy Hamilton, Renée Hoch
1Program in Developmental Biology, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Abstract:
A central issue in signal transduction is the physiological contribution of different growth factor-initiated signaling pathways. We have generated knockin mice harboring mutations in the PDGFalpha receptor (PDGFalphaR) that selectively eliminate its capacity to activate PI3 kinase (alpha(PI3K)) or Src family kinases (alpha(Src)). The alpha(PI3K) mutation leads to neonatal lethality due to impaired signaling in many cell types, but the alpha(Src) mutation only affects oligodendrocyte development. A third knockin line containing mutations that eliminate multiple docking sites does not increase the severity of the alpha(PI3K) mutation. However, embryos with mutations in the PI3K binding sites of both PDGFRs (alpha and beta) recapitulate the PDGFalphaR null phenotype. Our results indicate that PI3K has a predominant role in PDGFalphaR signaling in vivo and that RTK-activated signaling pathways execute both specific and overlapping functions during mammalian development.
Insights
Investigating platelet-derived growth factor receptor alpha (PDGFalphaR) signaling in mice revealed that PI3 kinase activation is crucial for development. Impairing this pathway led to neonatal lethality, highlighting its essential role in signal transduction.
Area of Science:
- Cellular signaling
- Developmental biology
- Molecular genetics
Background:
- Signal transduction pathways are critical for physiological processes.
- Understanding the specific roles of growth factor signaling is a central challenge.
Purpose of the Study:
- To elucidate the in vivo contribution of distinct signaling pathways initiated by the PDGFalpha receptor.
- To differentiate the roles of PI3 kinase and Src family kinases downstream of PDGFalphaR.
Main Methods:
- Generation of knockin mice with specific mutations in the PDGFalpha receptor.
- Selective elimination of PI3 kinase (alpha(PI3K)) or Src family kinase (alpha(Src)) activation sites.
- Analysis of developmental phenotypes and signaling capacities.
Main Results:
- The alpha(PI3K) mutation caused neonatal lethality, indicating PI3 kinase's vital role in multiple cell types.
- The alpha(Src) mutation selectively impaired oligodendrocyte development.
- Mutations affecting both PDGF alpha and beta receptors' PI3K binding sites mimicked the PDGFalphaR null phenotype.
Conclusions:
- PI3 kinase plays a predominant role in PDGFalphaR signaling in vivo.
- Receptor tyrosine kinase (RTK)-activated pathways exhibit both specific and overlapping functions during mammalian development.