G C A T T A C G G C A T genes Review Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective Peter M.J. Quinn 1 and Jan Wijnholds 1,2,* 1 Department of Ophthalmology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; [email protected] 2 The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands * Correspondence: [email protected]; Tel.: +31-71-526-9269 Received: 21 August 2019; Accepted: 26 November 2019; Published: 29 November 2019 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. Keywords: apical polarity; crumbs complex; fetal retina; PAR complex; retinal organoids; retinogenesis; gene augmentation; adeno-associated virus (AAV); Leber congenital amaurosis 1. The Physiology of Vision 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]. Vision begins with the processing of light, which is electromagnetic radiation that travels as waves (Figure1A). Light waves, as with all waves, can be characterized by their wavelength (distance between wave peaks), frequency (number of wavelengths within a time period), and amplitude (the height of each peak or depth of each trough). Visible light is a narrow group of wavelengths between approximately 400 nm and 760 nm which we interpret as a spectrum of different colors (Figure1B) [2]. Light can be reflected (bounce of a surface), absorbed (transfer of energy to a surface), or refracted (bending of light between two mediums) (Figure1C). Genes 2019, 10, 987; doi:10.3390/genes10120987 www.mdpi.com/journal/genes Genes 2019, 10, 987 2 of 40 Genes 2019, 10, 987 2 of 38 Figure 1. Transmission of light. (A) Light is electromagnetic radiation that travels as waves consisting of Figure 1. Transmission of light. (A) Light is electromagnetic radiation that travels as waves consisting perpendicular oscillating electric and magnetic fields. (B) Visible light is a narrow group of wavelengths of perpendicular oscillating electric and magnetic fields. (B) Visible light is a narrow group of between approximately 400 nm (short wavelength) and 760 nm (long wavelength) which we interpret aswavelengths a spectrum between of different approximately colors. Wavelengths 400 nm (short outside wavelength) this range and are 760 not nm visible (long to wavelength) humans. (C) which Light canwe interpret be reflected, as absorbeda spectrum and of refracted. different colors. Wavelengths outside this range are not visible to humans. (C) Light can be reflected, absorbed and refracted. When light first enters the eye, it is refracted by the cornea through the pupil, whose size is controlledWhen by light the first iris. 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