Modeling binary and graded cone cell fate patterning in the mouse retina

Abstract

Nervous systems are incredibly diverse, with myriad neuronal subtypes defined by gene expression. How binary and graded fate characteristics are patterned across tissues is poorly understood. Expression of opsin photopigments in the cone photoreceptors of the mouse retina provides an excellent model to address this question. Individual cones express S-opsin only, M-opsin only, or both S-opsin and M-opsin. These cell populations are patterned along the dorsal-ventral axis, with greater M-opsin expression in the dorsal region and greater S-opsin expression in the ventral region. Thyroid hormone signaling plays a critical role in activating M-opsin and repressing S-opsin. Here, we developed an image analysis approach to identify individual cone cells and evaluate their opsin expression from immunofluorescence imaging tiles spanning roughly 6 mm along the D-V axis of the mouse retina. From analyzing the opsin expression of~250,000 cells, we found that cones make a binary decision between S-opsin only and co-expression competent fates. Co-expression competent cells express graded levels of Sand M-opsins, depending nonlinearly on their position in the dorsal-ventral axis. M-and S-opsin expression display differential, inverse patterns. Using these single-cell data, we developed a quantitative, probabilistic model of cone cell decisions in the retinal tissue based on thyroid hormone signaling activity. The model recovers the probability distribution for cone fate patterning in the mouse retina and describes a minimal set of interactions that are necessary to reproduce the observed cell fates. Our study provides a paradigm describing how differential responses to regulatory inputs generate complex patterns of binary and graded cell fates.

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival

“…To further examine the pathological changes of cones in HKO mice, retinal flat mounts from young (5-month-old) animals were prepared and coimmunostained with an L/M-opsin antibody to mark the cone OS and Alexa Fluor-594-conjugated PNA. Given that the M-opsin-expressing cones were largely concentrated in the dorsal retina, with very few M-opsin-positive cones in the ventral retina [ 40 ], we quantified the OS length and the number of M-cones in the dorsal retina of HKO and control mice. As expected, a dramatic decrease in the number of M-cone cells was observed in the HKO retina (Fig.…”

Patterning and Development of Photoreceptors in the Human Retina

“…The COUP family of transcription factors also plays a role in the specification of cone subtype specification in mice. Mice have a gradient of cone subtypes with more M cones in the dorsal retina and more S cones in the ventral retina ( Wikler et al, 1996 ; Eldred et al, 2020 ). COUP-TFI suppresses M-opsin ventrally while COUP-TFI and COUP-TFII suppress S-opsin dorsally.…”

Retinal glial cells under hypoxia possibly function in mammalian myopia by responding to mechanical stimuli, affecting hormone metabolism and peptide secretion

“…Some of the functions have been experimentally proven, such as hormone regulation. Thyroid hormone signalling activity can decide the M/S-cone fate [35] . Matrix metalloproteinase 2 (MMP-2) is a widely recognised extracellular remodelling factor that is generally found in the retina and scleral tissue in myopia [36][37][38] .…”