Molecular anatomy of the developing human retina

Clinical and genetic heterogeneity associated with retinal diseases makes stem cell-based therapies an attractive strategy for personalized medicine. However, we have limited understanding of the timing of key events in the developing human retina, and in particular the factors critical for generating the unique architecture of the fovea and surrounding macula. Here we define three key epochs in the transcriptome dynamics of human retina from fetal day (D) 52 to 150. Coincident histological analyses confirmed the cellular basis of transcriptional changes and highlighted the dramatic acceleration of development in the fovea compared to peripheral retina. Human and mouse retinal transcriptomes show remarkable similarity in developmental stages, though morphogenesis was greatly expanded in humans. Integration of DNA accessibility data allowed us to reconstruct transcriptional networks controlling photoreceptor differentiation. Our studies provide insights into human retinal development and serve as resource for molecular staging of human stem cell-derived retinal organoids. Overall design: Whole human fetal retina samples [spanning 12 time points: D52/54, D53, D57, D67, D80, D94 (2 samples), D105, D107, D115, D125, D132 and D136] or dissected retinal regions [at four time points: D59 (periphery and central, 2 samples each), D73 (periphery and fovea/macula), D96 (periphery, fovea/macula, and nasal central) and D132 (periphery, fovea/macula, and nasal central)] were used to generate RNA-seq libraries.