Abstract
Retinal cells become post-mitotic early during post-natal development. It is likely that p53, a well-known cell cycle regulator, is involved in regulating the genesis, differentiation and death of retinal cells. Furthermore, retinal cells are under constant oxidative stress that can result in DNA damage, due to the extremely high level of metabolic activity associated with phototransduction. If not repaired, this damage may result in p53-dependent cell death and ensuing vision loss. In this study, the role of p53 during retinal development and in the post-mitotic retina is investigated. A previously described super p53 transgenic mouse that expresses an extra copy of the mouse p53 gene driven by its endogenous promoter is utilized. Another transgenic mouse (HIP) that expresses the p53 gene in rod and cone photoreceptors driven by the human interphotoreceptor retinoid binding protein promoter was generated. The electroretinogram (ERG) of the super p53 mouse exhibited reduced rod-driven scotopic a and b wave and cone-driven photopic b wave responses. This deficit resulted from a reduced number of rod photoreceptors and inner nuclear layer cells. However, the reduced photopic signal arose only from lost inner retinal neurons, as cone numbers did not change. Furthermore, cell loss was non-progressive and resulted from increased apoptosis during retinal developmental as determined by TUNEL staining. In contrast, the continuous and specific expression of p53 in rod and cone photoreceptors in the mature retinas of HIP mice led to the selective loss of both rods and cones. These findings strongly support a role for p53 in regulating developmental apoptosis in the retina and suggest a potential role, either direct or indirect, for p53 in the degenerative photoreceptor loss associated with human blinding disorders.
Highlights
The scotopic b wave was preceded by the negative-going a wave, which represents the collective response of the rods
The studies performed in the super p53 mouse indicate that developmental overexpression of p53 in the retina leads to the selective loss of rod photoreceptors, but leaves the cone photoreceptor population apparently intact
The selective loss of rods is consistent with the functional deficits shown by the diminished a and b waves of the rod-driven ERG in the super p53 mouse
Summary
P53 is a tumor suppressor that is activated in response to cellular stressors such as DNA damage, oncogene activation, and loss of contact between cells (for review [1]). We demonstrate that the super p53 mouse exhibits increased developmental retinal apoptosis, supporting an important role for p53 in retinal development This p53-induced developmental apoptosis decreased the total number of rod photoreceptors and postreceptoral neurons in the inner nuclear layer (INL), but did not induce loss of cone photoreceptors or any further progressive degeneration of retinal cells in the mature retina. These changes were reflected in the functional responses recorded from the super p53 mouse. To assess the effects of p53 expression in adult photoreceptors, and to test whether the site of transgene integration was important to p53 overexpression effects, retinal structure and function were examined in HIP transgenic mice, and corroborated the findings from the super p53 mouse
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