Pax6 modulates intra-retinal axon guidance and fasciculation of retinal ganglion cells during retinogenesis

Abstract

Intra-retinal axon guidance involves a coordinated expression of transcription factors, axon guidance genes, and secretory molecules within the retina. Pax6, the master regulator gene, has a spatio-temporal expression typically restricted till neurogenesis and fate-specification. However, our observation of persistent expression of Pax6 in mature RGCs led us to hypothesize that Pax6 could play a major role in axon guidance after fate specification. Here, we found significant alteration in intra-retinal axon guidance and fasciculation upon knocking out of Pax6 in E15.5 retina. Through unbiased transcriptome profiling between Pax6fl/fl and Pax6−/− retinas, we revealed the mechanistic insight of its role in axon guidance. Our results showed a significant increase in the expression of extracellular matrix molecules and decreased expression of retinal fate specification and neuron projection guidance molecules. Additionally, we found that EphB1 and Sema5B are directly regulated by Pax6 owing to the guidance defects and improper fasciculation of axons. We conclude that Pax6 expression post fate specification of RGCs is necessary for regulating the expression of axon guidance genes and most importantly for maintaining a conducive ECM through which the nascent axons get guided and fasciculate to reach the optic disc.

Exosomal circular RNA hsa_circ_007293 promotes proliferation, migration, invasion, and epithelial–mesenchymal transition of papillary thyroid carcinoma cells through regulation of the microRNA-653-5p/paired box 6 axis

“…Here, through miRTarBase, starBase, and miRDB analyses, we discovered that PAX6 might potentially target miR-653-5p, which was further confirmed by dual luciferase reporter assay. PAX6 belongs to the PAX family and is a vital transcription factor in a variety of biological processes [ 42 ]. Other investigations have also supported PAX6 as an oncogene and have characterized its overexpression across numerous types of human cancers [ 43 , 44 ].…”

Human Foveal Cone and RPE Cell Topographies and Their Correspondence With Foveal Shape

“…33 , 35 , 57 – 59 In Pax6 and albino mouse models, it has been shown that the ability of the RPE to produce pigment also alters the genesis of retinal ganglion cells, their subpopulation fate, and optic nerve routing. 60 , 61 Some common allelic variants in genes associated with oculocutaneous albinism have also been linked to minor degrees of foveal hypoplasia. 62 Furthermore, inter-individual differences in retinal melanin have been linked to differences in foveal shape, with African and African American individuals having a wider and deeper pit than Caucasian individuals.…”

Features of Retinal Neurogenesis as a Key Factor of Age-Related Neurodegeneration: Myth or Reality?

“…Mutation of Pax6 or its overexpression leads to several pathological phenotypes: cataract, aniridia, or the absence of the eye in mice and humans [75]. When Pax6 is inactivated in all retinal cells starting from E15.5, the numbers of retinal ganglion cells, amacrine cells, horizontal cells, and photoreceptors drastically decrease as compared to control mice [76].…”

“…Moreover, the expression of many genes that are essential for retinal development is severely affected by PAX6 loss. In this regard, the most important genes are NeuroD1, Neu-roD4, Nr2e3, Rp1, Prph2, and Rho, whose products are involved in fate specification of retinal neurons [76]. On the other hand, Pax6 overexpression can yield aberrant axonal patterns where axons fail to navigate toward the optic chiasm [77].…”

“…On the other hand, Pax6 overexpression can yield aberrant axonal patterns where axons fail to navigate toward the optic chiasm [77]. A recent report showed that Pax6 expression after fate specification of retinal ganglion cells is necessary for the regulation of expression of axon guidance genes and most importantly for the maintenance of conducive extracellular-matrix molecules through which the nascent axons get guided and fasciculate to reach the optic disc [76]. further differentiation of ganglion cells, and MATH5 expression decreases afterwards [82].…”