Electroretinographic Findings in Knockin Mice With Gain of Function and Loss of Function Erythropoietin Receptor Signaling

Abstract

Purpose: : A growing body of evidence suggests that erythropoietin (Epo) plays a role in angiogenesis and neuroprotection. To investigate the possible role of erythropoietin in the retina we performed electroretinography in transgenic mice with gain-of-function and loss-of-function erythropoietin receptors (EpoR).

Methods: : The animal models of increased and decreased Epo signaling were previously generated by homologous recombination in mouse embryonic stem cells. The murine EpoR gene was replaced with a gain-of-function mutant human EPOR (mthEPOR, from a patient with primary familial polycythemia) and with a loss-of-function wild-type human EPOR gene (wthEPOR) (PNAS, 98:986, 2001). 3 mthEPOR and 4 wthEPOR homozygotes underwent simultaneous bilateral dark-adapted electroretinography at 4 and 12 months of age.

Results: : At 4 months mthEPOR mice had a greater saturated a-wave amplitude compared to wthEPOR mice (510±31µV (mean±SEM) compared to 410±26µV, p=0.034), while the difference in maximum b-wave amplitude did not reach statistical significance (mthEPOR mice 490±38µV compared to wthEPOR 437±37µV). At 12 months mthEPOR mice had a statistically greater maximum b-wave amplitude compared to wthEPOR (400±8µV compared to 232±17µV, p=0.0006) mice while the difference in saturated a-wave amplitude failed to reach statistical significance (452±27µV compared to 367±21µV, p=0.21).

Conclusions: : The greater a- and b- wave amplitudes found in the gain-of-function EpoR signaling mice may indicate that erythropoietin is a neurotrophic factor in the neurosensory retina. Histological analyses may corroborate structural differences that account for our electroretinographic findings.

Keywords: neuroprotection • electroretinography: clinical • growth factors/growth factor receptors