Covello Giuseppina, Rossello Fernando J, Filosi Michele, Gajardo Felipe, Duchemin Anne-Laure, Tremonti Beatrice F, Eichenlaub Michael, Polo Jose M, Powell David, Ngai John, Allende Miguel L, Domenici Enrico, Ramialison Mirana, Poggi Lucia
Department of Cellular, Computational and Integrative Biology - CIBIO University of Trento Trento Italy.
Present address: Department of Biology University of Padova Padova Italy.
FASEB Bioadv. 2020 Jun 27;2(7):434-448. doi: 10.1096/fba.2020-00030. eCollection 2020 Jul.
Expression of the bHLH transcription protein Atoh7 is a crucial factor conferring competence to retinal progenitor cells for the development of retinal ganglion cells. Several studies have emerged establishing as a retinal disease gene. Remarkably, such studies uncovered variants associated with global eye defects including optic nerve hypoplasia, microphthalmia, retinal vascular disorders, and glaucoma. The complex genetic networks and cellular decisions arising downstream of expression, and how their dysregulation cause development of such disease traits remains unknown. To begin to understand such Atoh7-dependent events in vivo, we performed transcriptome analysis of wild-type and mutant () zebrafish embryos at the onset of retinal ganglion cell differentiation. We investigated in silico interplays of and other disease-related genes and pathways. By network reconstruction analysis of differentially expressed genes, we identified gene clusters enriched in retinal development, cell cycle, chromatin remodeling, stress response, and Wnt pathways. By weighted gene coexpression network, we identified coexpression modules affected by the mutation and enriched in retina development genes tightly connected to . We established the groundwork whereby Atoh7-linked cellular and molecular processes can be investigated in the dynamic multi-tissue environment of the developing normal and diseased vertebrate eye.
bHLH转录蛋白Atoh7的表达是赋予视网膜祖细胞发育为视网膜神经节细胞能力的关键因素。已有多项研究表明它是一种视网膜疾病基因。值得注意的是，这些研究发现了与包括视神经发育不全、小眼症、视网膜血管疾病和青光眼在内的全身性眼部缺陷相关的变异。Atoh7表达下游产生的复杂遗传网络和细胞决策，以及它们的失调如何导致这些疾病特征的发展仍然未知。为了开始在体内理解此类依赖Atoh7的事件，我们在视网膜神经节细胞分化开始时对野生型和Atoh7突变型（Atoh7−/−）斑马鱼胚胎进行了转录组分析。我们研究了Atoh7与其他疾病相关基因和通路的计算机模拟相互作用。通过对差异表达基因的网络重建分析，我们确定了富含视网膜发育、细胞周期、染色质重塑、应激反应和Wnt通路的基因簇。通过加权基因共表达网络，我们确定了受突变影响且富含与Atoh7紧密相连的视网膜发育基因的共表达模块。我们奠定了基础，据此可以在发育中的正常和患病脊椎动物眼睛的动态多组织环境中研究与Atoh7相关的细胞和分子过程。
