Purchase this article with an account.
Pamela S Lagali, Chantal Medina, Keqin Yan, Adam Baker, Stuart G Coupland, Valerie A Wallace, David Picketts; The Atrx Chromatin Remodeler is Required in Retinal Bipolar Cells for Amacrine and Horizontal Cell Survival. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2637.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The success of photoreceptor repair or replacement strategies for the treatment of retinal degenerative diseases critically depends on the continued survival and function of the inner retinal neurons. Morphological defects and death of these neurons are known to occur in later stages of retinal degeneration and may limit the effectiveness of long-term therapies for vision restoration. We have shown that the chromatin remodeling protein Atrx is important for the maintenance and function of amacrine and horizontal cells. We aim to understand the mechanism by which Atrx activity mediates retinal inhibitory interneuron survival.
Atrx was deleted in different retinal cell populations by generating cell type-specific conditional knockout mice via Cre recombinase-mediated genetic excision using germline transgenic and in vivo electroporation approaches. Morphological, functional, and genetic analysis of the Atrx-deleted retinas was performed using immunohistochemistry and fluorescence microscopy, electroretinography, and quantitative RT-PCR respectively.
Amacrine and horizontal cell disorganization and loss occurs when Atrx is deleted in multipotent progenitor cells during embryonic retinal development, but not when the gene is inactivated in lineage-restricted, post-mitotic amacrine and horizontal precursor cells. Selective genetic ablation of Atrx postnatally in retinal bipolar cells recapitulates the effects of early pan-retinal gene deletion, indicating that Atrx activity in these neurons is responsible for the function and survival of the retinal inhibitory interneurons. Further genetic and immunohistochemical analysis of the mutant mice reveals dysregulation of bipolar cell marker genes, misexpression of bipolar subtype-specific proteins, and alterations in neuronal morphology that may underlie defects in inner retinal circuitry.
The loss of amacrine and horizontal cells from Atrx-deleted retinas appears to occur through a non-cell autonomous mechanism. Our analyses implicate a role for bipolar cells in retinal inhibitory interneuron survival and function. Atrx-mediated chromatin remodeling may be important for the regulation of specific genes that are involved in retinal neuron synaptic activity, connectivity, and homeostasis. These genes may represent potential targets of neuroprotective strategies for retinal degenerative disease therapies.
This PDF is available to Subscribers Only