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Frs2α enhances fibroblast growth factor-mediated survival and differentiation in lens development

Bhavani P Madakashira1, Daniel A Kobrinski, Andrew D Hancher

  • 1Department of Zoology, Miami University, Oxford, OH 45056, USA.

Development (Cambridge, England)
|November 9, 2012
PubMed

Insights

Fibroblast growth factor receptors (Fgfrs) uniquely drive lens fiber cell differentiation by activating the signaling molecule Frs2α. This pathway is crucial for lens cell survival and differentiation, even when other receptor tyrosine kinases are involved.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Molecular Signaling

Background:

  • Receptor tyrosine kinases (RTKs) activate similar intracellular pathways (Erk1/2, PI3-K/Akt) but yield diverse biological outcomes.
  • Lens epithelial cells express multiple RTKs, yet only Fibroblast growth factor receptors (Fgfrs) induce lens fiber cell differentiation.
  • Frs2α is a key signal transduction molecule activated by Fgfrs specifically within the lens.

Purpose of the Study:

  • To elucidate the mechanism by which RTK stimulation is channeled to specific biological responses, focusing on lens fiber cell differentiation.
  • To determine the role of Frs2α in Fgfr-mediated lens cell differentiation and survival.
  • To investigate if other RTKs can induce lens fiber cell differentiation via Frs2α.

Main Methods:

  • Analysis of Frs2α-deficient mouse lenses to assess apoptosis, Erk1/2 and Akt phosphorylation, and expression of differentiation markers (Prox1, p57KIP2, aquaporin 0, β-crystallins).
  • Generation of transgenic mouse lenses expressing TrkC (an RTK) and its ligand NT3.
  • Evaluation of phenotypic changes in transgenic lens epithelial cells, including cell morphology, signaling pathway activation, and marker expression, with and without Frs2α.

Main Results:

  • Loss of Frs2α in the lens led to increased apoptosis, reduced Erk1/2 and Akt phosphorylation, and decreased expression of lens fiber cell differentiation markers.
  • Expression of TrkC and NT3 in transgenic lenses induced lens fiber cell characteristics, such as elongation, enhanced Erk1/2 and Akt phosphorylation, and β-crystallin expression.
  • These NT3-TrkC-induced changes were dependent on Frs2α, demonstrating its critical role in mediating the effects.

Conclusions:

  • Tyrosine phosphorylation of Frs2α is essential for Fgfr-dependent lens cell survival.
  • Frs2α activation by RTKs provides a mechanistic basis for the unique capacity of Fgfs to induce mammalian lens fiber cell differentiation.
  • This study highlights Frs2α as a central mediator in channeling RTK signals for specific developmental outcomes in the lens.

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