Chapter 1
Historical Perspectives
Hisato Kondoh
1, and Robin Lovell-Badge
2 1Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan 2The Crick Institute, London, UKAbstract
A quarter of century has passed since the discovery of the first Sox gene, SRY/Sry. Shortly afterward, many related Sox genes encoding SOX family transcription factors were identified. The importance of their role in development and diseases has attracted growing attention. Among the Sox transcription factor genes, the role of Sox2 has been highlighted mostly for its involvement in early developmental processes and organogenesis, and in particular for its central role in regulating a wide spectrum of stem cells. A historical overview is provided here concerning how molecular actions of SOX2 have been clarified to account for its participation in a wide range of biological processes.
Keywords
Chromatin regulation; Enhancers; Oncogenesis; Organogenesis; Partner factor interaction; Stem cells
A quarter of century has passed since the discovery of the first Sox gene, SRY/Sry. Shortly afterward, many related Sox genes encoding SOX family transcription factors were found to be distributed in the genome. The importance of their role in development and diseases has attracted growing attention. Among the Sox transcription factor genes, the role of Sox2 has been highlighted mostly for its involvement in early developmental processes and organogenesis, and in particular for its central role in regulating a wide spectrum of stem cells.
In the investigation of various transcription factors involved in the developmental process, SOX2 research has always been on the leading edge and has provided a paradigm of their action from molecular to organismal dimensions. Through scientific processes in which basic problems have been answered concomitantly with the rise of new questions, we are in the position to grasp an overall view of Sox2 and SOX2 functions across the dimensions. In this book, our current understanding is dismantled into individual dimensions for readers to synthesize them for their own study.
This chapter aims to familiarize readers with the history of SOX2 research over the past quarter century and highlights landmark findings and topics. We hope that readers will appreciate how the multifaceted functions
Sox2 are derived from the unique basic features of the SOX2 molecule and from multilayered
Sox2 regulation (
Table 1).
Discovery of SOX2 and other Sox Genes Pioneered by Sry
The identification of
SRY/
Sry as a male-specifying gene marked a breakthrough not only in sex determination research but also in the area of genetic regulation of embryonic development (
Gubbay et al., 1990;
Sinclair et al., 1990). Shortly after this discovery, many genes sharing the High Mobility Group (HMG) box sequences similar to
Sry were identified in the genome and were found to be expressed in embryos (
Gubbay et al., 1990;
Denny et al., 1992). These genes were named
Sox (
Sry-related HMG box) genes. Their HMG box sequences were similar to those of Lef/Tcf family transcription factors discovered around the same time, but
Sox genes formed a clearly distinct gene group, as detailed in
Chapter 6. The SOX proteins were characterized as deoxyribonucleic acid (DNA)-binding transcription factors because of their binding to (A)ACAA[A/T](G) sequences and their possession of activation or repression domains (
Kamachi and Kondoh, 2013).
Table 1
Chronological table of Sox2 research
| Tissue-specific expression of SoxB1 genes | 1994 | |
Remarkably, some
Sox genes, in particular those with HMG box sequences closest to
SRY, initially called a1 to a3 and now called
Sox1,
Sox2, and
Sox3, respectively, and classified as
SoxB1 genes (
Bowles et al., 2000), were found to be expressed in a highly tissue-specific manner in mouse embryos. This strongly suggests their involvement in the regulation of cell and tissue differentiation processes (
Collignon et al., 1996;
Kamachi et al., 1998). A description of how these genes came to be named was provided by
Lovell-Badge (2010). Expression data from the chicken version of
Sox1 to
Sox3 also emphasized the association of these genes with developmental processes (
Uwanogho et al., 1995;
Uchikawa et al., 1999).
In 1996, the
Drosophila Dichaete gene (also called
fish-hook), identified by mutants defective in embryonic processes, was found to code for a
Sox gene (
Nambu and Nambu, 1996;
Russell et al., 1996) that is now classified as
SoxB1 (
Phochanukul and Russell, 2010). These observations clearly indicated that
Sox2 and other
Sox genes participate in developmental regulations not only in vertebrates but also in a wide range of animal species (
Pevny and Lovell-Badge, 1997). Phylogenetic aspects of
SoxB1 gene evolution are given in
Chapter 6.
SOX2 with Defined Regulatory Targets, in Cooperation with Partner Factors
SOX2 was one of the transcription factors involved in the developmental processes whose regulatory target genes were identified earliest. Significant discoveries were made in 1995. Lisa Dailey and colleagues investigated
fibroblast growth factor 4 (
Fgf4) activation in teratocarcinoma (and later embryonic stem (ES)) cell lines and found that SOX2 and OCT3 (a synonym of OCT4 and renamed as POU5F1 by the Mouse Genome Informatics Consortium) cooperate in the activation of the
Fgf4 enhancer bearing their juxtaposed binding sites (
Yuan et al., 1995). We identified SOX2 as the major regulator of
δ- and
γ-crystallin genes specifically expressed in the lens (
Kamachi et al.,... 
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