Abstract
ABSTRACTThe scarcity of embryonic/foetal material as a resource for direct study means that there is still limited understanding of human retina development. Here, we present an integrated transcriptome analysis combined with immunohistochemistry in human eye and retinal samples from 4 to 19 post-conception weeks. This analysis reveals three developmental windows with specific gene expression patterns that informed the sequential emergence of retinal cell types and enabled identification of stage-specific cellular and biological processes, and transcriptional regulators. Each stage is characterised by a specific set of alternatively spliced transcripts that code for proteins involved in the formation of the photoreceptor connecting cilium, pre-mRNA splicing and epigenetic modifiers. Importantly, our data show that the transition from foetal to adult retina is characterised by a large increase in the percentage of mutually exclusive exons that code for proteins involved in photoreceptor maintenance. The circular RNA population is also defined and shown to increase during retinal development. Collectively, these data increase our understanding of human retinal development and the pre-mRNA splicing process, and help to identify new candidate disease genes.
Highlights
The development of the human eye and the visual system is a complex process that has attracted great interest throughout history (Heavner and Pevny, 2012; Reeves and Taylor, 2004)
After quality control and normalisation of the data, we investigated how the overall expression of protein-coding genes changed during development
DISCUSSION embryonic studies are widespread in other mammalian organisms and these have contributed greatly to our knowledge, characterising the events that occur during human development is crucial in order to identify the differences that exist between humans and other organisms, and to better understand the pathogenesis of many forms of human disease arising from mutations in genes implicated in early development (Wadman, 2015; Hayden, 2016)
Summary
The development of the human eye and the visual system is a complex process that has attracted great interest throughout history (Heavner and Pevny, 2012; Reeves and Taylor, 2004). Human eye development begins at post conception week (PCW) 3.5 and continues until the 5th postnatal month. It begins with the expression of a set of transcription factors (TFs) within the neuroectodermal plate known as the eye field (Zuber et al, 2003). The optic vesicles undergo complex patterning and morphogenesis, with the distal optic vesicle developing into neural retina with cell fate decisions following the order of retinal histogenesis. The vertebrate retina is composed of five neuronal and one glial cell type (Müller glia) that are organized within three different layers. Each of the retinal cell types is generated in an orderly manner that has been well studied in vertebrates (Marquardt and Gruss, 2002)
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