Prdm13Regulates Subtype Specification of Retinal Amacrine Interneurons and Modulates Visual Sensitivity

Abstract

Amacrine interneurons, which are highly diversified in morphological, neurochemical, and physiological features, play crucial roles in visual information processing in the retina. However, the specification mechanisms and functions in vision for each amacrine subtype are not well understood. We found that the Prdm13 transcriptional regulator is specifically expressed in developing and mature amacrine cells in the mouse retina. Most Prdm13-positive amacrine cells are Calbindin-and Calretinin-positive GABAergic or glycinergic neurons. Absence of Prdm13 significantly reduces GABAergic and glycinergic amacrines, resulting in a specific defect of the S2/S3 border neurite bundle in the inner plexiform layer. Forced expression of Prdm13 distinctively induces GABAergic and glycinergic amacrine cells but not cholinergic amacrine cells, whereas Ptf1a, an upstream transcriptional regulator of Prdm13, induces all of these subtypes. Moreover, Prdm13-deficient mice showed abnormally elevated spatial, temporal, and contrast sensitivities in vision. Together, these results show that Prdm13 regulates development of a subset of amacrine cells, which newly defines an amacrine subtype to negatively modulate visual sensitivities. Our current study provides new insights into mechanisms of the diversification of amacrine cells and their function in vision.

Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy

“…PRDM13 has been shown to be expressed in hindbrain, spinal cord, retina, and olfactory placode, in developing zebrafish (Sun et al, ). In the mouse, expression is reported in dorsal spinal cord progenitor (Kinameri et al, ) and retinal amacrine cells, with a role in determining excitatory and inhibitory neurons (Mona et al, ; Watanabe et al, ). PRDM13 is also found highly transcribed in microarray data from fetal human retina (Kozulin & Provis, ).…”

“…Overexpression models suggest that PRDM13 has a toxic effect on photoreceptors in prenatal mice with no perturbation of amacrine cell lineages (Goodson et al, ); it was also shown to impair eye development in Drosophila and Xenopus (Bessodes, Parain, Bronchain, Bellefroid, & Perron, ; Manes et al, ). Conversely, murine knockout of Prdm13 results only in alteration of amacrine cell development without functional vision loss (Watanabe et al, ). Nevertheless, the effect of the disease associated variants on the expression of PRDM13 remains to be characterised.…”

Duplication events downstream ofIRX1cause North Carolina macular dystrophy at the MCDR3 locus

“…The lack of readily accessible animal or in vitro models has hindered detailed understanding of macular development, as this structure only evolved in higher primates among mammals. Recently, disrupted developmental expression of the transcription factor and histone methyltransferase PRDM13 29,30 was suggested as a disease mechanism for NCMD at the 6q16 locus, based on the identification of non-coding SNVs and duplication events residing in an overlapping region upstream of PRDM13 in many MCDR1 families. Differential regulation of PRDM13 in eyecups derived from wild-type iPSCs 15,16 was suggested.…”

How lateral inhibition and fast retinogeniculo-cortical oscillations create vision: A new hypothesis

“…In order for rod bipolar cells to communicate with ON-and OFF-ganglion cells, they must use AII amacrine cells [24,25]. Amacrine interneurons are highly diversified and are essential for processing visual information in the retina [26]. Amacrine cells not only release glutamate signals received by the special receptors (eye-enriched kainate receptors) in photoreceptors, but their feedback regulation is responsible for maintaining light sensitivity in ambient light [27].…”