Interplay of Pax6 and SOX2 in lens development as a paradigm of genetic switch mechanisms for cell differentiation

Abstract

When the cloning era arrived, our first target for cloning was the δ δ δ δ δ1-crystallin gene of the chicken, the lens-specific gene expressed earliest following lens induction. We have investigated the regulation of this gene with the idea that the mechanism of its activation must reflect that of lens differentiation per se. We here summarize the investigation carried out in our group along this line over the past 20 years. The δ δ δ δ δ1-crystallin gene is regulated by an enhancer in the third intron, and the specificity of this regulation is governed by a DNA region (called DC5) of only 30 bp DNA bound by two transcription factors. These factors have been identified as SOX1/2/3 (Group B1 SOX proteins, SOX2 being the major player) and Pax6, and have been shown to bind cooperatively to DC5 and form a ternary complex having a robust potency for transcriptional activation. In the embryo, Pax6 is widely expressed in the head ectoderm before the lens is formed, and as the optic vesicle comes into contact with the ectoderm, SOX2/3 expression is induced in the contacted area of the ectoderm, thereby allowing Pax6 and SOX2/3 to meet in the same cell nucleus, where they can then activate a battery of genes for early lens development including δ δ δ δ δ1- PreludeEye lenses are derived from head ectoderm, being induced by an effect of the optic vesicle, the retinal primordia extruding from the embryonic diencephalon. Lens develops as a remarkably transparent tissue, rich in a group of proteins collectively called crystallins. Crystallins are excellent molecular markers of lens differentiation, and have made it possible to study ectodermderived lens development as a paradigm of tissue differentiation. During the early period of modern cell differentiation studies, when cell types began to be defined on the basis of specific molecular constituents of the cells, specific anti-crystallin antibodies provided the sharpest molecular tools for the analysis of lens differentiation (Clayton and Truman, 1967;Clayton, 1970). Later, Rot analysis of crystallin cDNAs became available, and the beautiful work using this technique done by Shinohara and Piatigorsky (Shinohara and Piatigorsky, 1976) was the prelude of the real modern age of the study of lens development. Their work demonstrated that the δ1-crystallin gene is activated soon after the lens is induced in the head ectoderm by contact with the optic vesicle (retina primordium) extruding from the diencephalons. This also corroborated earlier immunochemical observations that δ1-crystallin is the first crystallin synthesized in lens development.The cloning age and δ1 δ1 δ1 δ1 δ1-crystallin regulation Then the cloning age arrived. Our first target of gene cloning was the δ1-crystallin gene of the chicken, because it was the earliest lensspecific gene to be turned on after lens induction. The idea behind this was that the mechanism of activating this gene must be deeply involved in the early process of lens differentiation, perhaps the lens induction process itself. Once th...

Pax6 is misexpressed in Sox1 null lens fiber cells

“…The central role that Pax6 plays in lens development and its relationship with another GroupB1 SRY-like HMG box protein, Sox2, is well documented (Kamachi et al, 2001;Aota et al, 2003;Kondoh et al, 2004;Donner et al, in press). Pax6 is upstream of Sox2 (Furuta and Hogan, 1998), Pax6 and Sox2 cooperatively regulate gene expression (Kamachi et al 2001, Aota et al, 2003, and Sox2 is required for the maintenance of Pax6 (Donner et al, in press).…”

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

“…Therefore, Sox2 also plays an essential context-dependent role in the CNS. Sox2 forms a complex with its partners to function, and Pax6 is one of the factors that interact with Sox2 in both stem/progenitor cells (eg, NSCs in the CNS and optic cup progenitor cells) and terminally differentiated cells (eg, lens cells) [16,[47][48][49]. In the OE, Pax6 and Sox2 are coexpressed in HBCs, GBCs, and SUSs, and they are believed to suppress neuronal differentiation [6].…”

Genetic and epigenetic mechanisms of gene regulation during lens development

“…In zebrafish mutant you-too (yot), isolated lenses develop from the adenohypophysal placode (Kondoh et al, 2000). The molecular mechanism of this mutation is the formation of a dominant negative Gli-2 mutant that attenuates hh signaling (see Kondoh et al, 2004). In addition, the primordium of the chicken anterior pituitary transiently expresses δ1-crystallin .…”