OTX2 Non-Cell Autonomous Activity Regulates Inner Retinal Function

Abstract

OTX2 is a homeoprotein transcription factor expressed in photoreceptors and bipolar cells in the retina. OTX2, like many other homeoproteins, transfers between cells and exerts non-cell autonomous effects such as promoting the survival of retinal ganglion cells that do not express the protein. Here we used a genetic approach to target extracellular OTX2 in the retina by conditional expression of a secreted single-chain anti-OTX2 antibody. Compared with control mice, the expression of this antibody by parvalbumin-expressing neurons in the retina is followed by a reduction in visual acuity in 1-month-old mice with no alteration of the retinal structure or cell type number or aspect. The a-waves and b-waves measured by electroretinogram were also indistinguishable from those of control mice, suggesting no functional deficit of photoreceptors and bipolar cells. Mice expressing the OTX2-neutralizing antibody did show a significant doubling in the flicker amplitude and a reduction in oscillatory potential, consistent with a change in inner retinal function. Our results show that interfering in vivo with OTX2 non-cell autonomous activity in the postnatal retina leads to an alteration in inner retinal cell functions and causes a deficit in visual acuity.

ENGRAILED-1 transcription factor has a paracrine neurotrophic activity on adult spinal α-motoneurons

“…Sample size estimate was based on our previous observations 15 . Results are expressed as mean ± SD.…”

“…16.504081 doi: bioRxiv preprint neural tube and guides Cajal-Retzius cell migration in the mouse neuroepithelium [10][11][12] . At late developmental stages and in the adult, OTX2 non-cell autonomous activity regulates cerebral cortex plasticity 13,14 , inner retinal physiological functions and RGC survival [15][16][17] . This novel signaling pathway is likely common to a larger number of HPs since the transfer domains are highly conserved between most HPs 18 .…”

“…ENGRAILED-2 and VAX1 respectively regulate retinal ganglion cell (RGC) axon guidance in the tectum and decussation at the optic chiasma [6][7][8][9] , while PAX6 regulates the size of the zebrafish eye anlagen, enhances oligodendrocyte progenitor cell migration in the chick neural tube, and guides Cajal-Retzius cell migration in the mouse neuroepithelium [10][11][12] . At late developmental stages and in the adult, OTX2 non-cell autonomous activity regulates cerebral cortex plasticity 13,14 , inner retinal physiological functions and RGC survival [15][16][17] . This novel signaling pathway, involving unconventional secretion and internalization with direct access to the cytoplasm, is likely common to a larger number of HPs since the transfer domains are highly conserved between most HPs 18 .…”

Unconventional Secretion, Gate to Homeoprotein Intercellular Transfer

“…Still for OTX2, its transfer within the retina from producing cells, probably bipolar neurons, to RGCs was demonstrated ( Sugiyama et al, 2008 ) and from the retinal pigmented epithelium (RPE) to photoreceptors strongly suggested ( Pensieri et al, 2021 ). The neutralization of extracellular OTX2 by an OTX2-scFv secreted by retinal parvalbumin producing cells leads to a decrease of visual acuity associated with the alteration of inner retinal functions and Otx2 knock out, specifically in the RPE, leads to photoreceptor cell death ( Torero Ibad et al, 2020 ; Pensieri et al, 2021 ). This putative trophic OTX2 activity was verified in the glaucoma model of induced excitotoxicity in the retina rapidly followed by RGC degeneration ( Torero Ibad et al, 2011 ).…”

Single-Cell Transcriptomic Profiling of Human Retinal Organoids Revealed a Role of IGF1-PHLDA1 Axis in Photoreceptor Precursor Specification

“…For example, OTX2 is expressed in nascent and mature photoreceptors and bipolar cells. 15 , 16 Conditional knockout of Otx2 results in complete loss of cones and rods, as well as a loss of bipolar cells in mice. 17 The transcriptional repressor Blimp1 (Prdm1) is expressed solely by Otx2+ cells and promotes nascent Otx2+ cell differentiated to photoreceptor cells by repressing bipolar fate.…”