Abstract
The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation.
Highlights
The Physiology of VisionVision is perhaps the most dominant sense in daily life and both non-correctable unilateral and bilateral vision loss severely impact the quality of life [1]
The developing mammalian retina expresses both CRB1 and CRB2. Both CRB1 and CRB2 are expressed at the subapical region adjacent to adherens junctions of progenitor cells at embryonic day 12.5 (Figure 7A), which is equivalent to the early 1st trimester human fetal retinal development, transcriptionally [40,41,232,242,269]
That in the absence of photoreceptor segments there is an increased bioavailability of associated virus (AAV) vectors, allowing targeting of less-abundant/preferred receptors for AAV uptake; (2) that there may be a common mechanism of active AAV uptake to photoreceptors through there segments, e.g., putative sites of receptor-dependent or -independent clathrin- and caveolae-mediated endocytosis; (3) that intact photoreceptor segments allow for efficient AAV5 gene therapy vector transduction of human photoreceptors, whereas loss of intact photoreceptor segments allows for efficient AAV5 gene therapy vector transduction of Müller glial cells [129]
Summary
Vision is perhaps the most dominant sense in daily life and both non-correctable unilateral and bilateral vision loss severely impact the quality of life [1]. Müller glial cells mediate the channelling of light through negatively affect the of photoreceptors, resulting in progressive loss of rod wavelengths and/or cone the retina towards thefunction photoreceptors [11,12]. Müller glial cells can channel different wavelengths of light to specific subsets photoreceptors contain an opsin protein covalently linked to the chromophore 11-cis-retinal. This active intermediate leads to triggering of a transduction cascade resulting in hyperpolarisation of the photoreceptors, due to the closure of cyclic guanosine closure of cyclic guanosine 30 ,50 -monophosphate (cGMP)-gated channels, and a reduction in glutamate release [14] This electrophysiological signal is further propagated to the inner retina and can be propagated through many different pathways to the ganglion cells. Visual acuity [17,18,19]
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