Aberrant gene expression yet undiminished retinal ganglion cell genesis in iPSC-derived models of optic nerve hypoplasia

作者：Jennifer G. Aparicio, Hanno Hopp, Narine Harutyunyan, Carly Stewart, David Cobrinik, Mark Borchert · 发表于：Ophthalmic Genetics · 年份：2023 · DOI：10.1080/13816810.2023.2253902 · 被引用次数：5 · 研究领域：Retinal Development and Disorders、Ocular Disorders and Treatments、Retinopathy of Prematurity Studies

Background Optic nerve hypoplasia (ONH), the leading congenital cause of permanent blindness, is characterized by a retinal ganglion cell (RGC) deficit at birth. Multifactorial developmental events are hypothesized to underlie ONH and its frequently associated neurologic and endocrine abnormalities; however, environmental influences are unclear and genetic underpinnings are unexplored. This work investigates the genetic contribution to ONH RGC production and gene expression using patient induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs).Materials and methods iPSCs produced from ONH patients and controls were differentiated to ROs. RGC genesis was assessed using immunofluorescence and flow cytometry. Flow-sorted BRN3+ cells were collected for RNA extraction for RNA-Sequencing. Differential gene expression was assessed using DESeq2 and edgeR. PANTHER was employed to identify statistically over-represented ontologies among the differentially expressed genes (DEGs). DEGs of high interest to ONH were distinguished by assessing function, mutational constraint, and prior identification in ONH, autism and neurodevelopmental disorder (NDD) studies.Results RGC genesis and survival were similar in ONH and control ROs. Differential expression of 70 genes was identified in both DESeq2 and edgeR analyses, representing a ~ 4-fold higher percentage of DEGs than in randomized study participants. DEGs showed trends towards over-representation of validated NDD genes and ONH e...