In 1990, Sinclair et al. first cloned the sex-determining gene SRY (Sex-determining Region of Y chromosome) located on the human Y chromosome. The SRY gene, known as SRY in humans and Sry in other animals, is located at Yp11.3. Many homologous genes to the Sry gene have been discovered in both mammalian and non-mammalian species. These genes share a common feature—a conserved sequence coding for 79 amino acids, known as the HMG box (High Mobility Group box), named for its rapid migration in electrophoresis. Genes encoding products with over 60% amino acid sequence similarity to the Sry gene product in the HMG box region are named SOX (in humans) or Sox (in other animals). The conserved HMG box in Sox genes can specifically bind to DNA sequences and exhibit spatial variability. The proteins encoded by Sox genes are important transcriptional regulators, playing critical roles in sex determination and differentiation, early embryonic development, nervous system development, cartilage formation, and the formation of various tissues and organs. Additionally, mutations or deletions in Sox genes can lead to developmental abnormalities or congenital diseases.

Figure 1. A schematic representation of the protein structures and domains of human SOX family members. (Saleem M, et al., 2022)

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Characteristics of Sox Genes

Over 100 Sox genes have been cloned from various species, including mammals, birds, reptiles, fish, and insects. The amino acid sequence of the HMG box region in Sox genes is highly conserved from humans to fruit flies, indicating the critical role of Sox family genes in testicular and other tissue differentiation and development across species. All known Sox genes can be categorized into 10 different subfamilies (A, B, C, D, E, F, G, H, I, and J) based on the homology of their HMG boxes. The general characteristics of Sox genes include:

1. Presence of HMG Box Motif: The products of these genes share over 60% sequence similarity with the SRY/Sry gene, with over 80% similarity within subfamilies and less similarity between subfamilies.

2. Sequence-Specific Recognition: For example, SRY protein recognizes the core sequence AACAATG through interactions with nucleotides in the DNA double helix minor groove, causing target DNA to bend. It can also bind to cross-shaped DNA in a non-sequence-specific manner.

3. Involvement in Developmental Gene Families: Sox genes are expressed in various tissues during embryonic development with temporal and spatial specificity, and some genes are also expressed in specific adult tissues.

4. Transcription Factor Encoding: Sox proteins regulate target gene expression by forming complexes with other transcription factors or ligand proteins.

5. Functional Diversity: A single Sox gene can affect different promoters in various cells or within the same cell. Some Sox genes have overlapping functions and can substitute for each other.

6. Complex Regulatory Networks: During developmental regulation, Sox genes interact with other regulatory genes to form a complex network rather than a simple linear cascade.

7. High Evolutionary Conservation: Amino acid sequence similarity between different Sox genes within the same species is limited to the HMG box region, while the same Sox gene in different species may have other similar regions outside the HMG box.

8. Scattered Distribution in the Genome: Sox family genes are dispersed throughout the genome. Most Sox genes lack introns, though a few, such as those in subfamilies D, E, and F, contain introns within the HMG box.

Functions of Sox Genes

Sox gene-encoded proteins bind to specific DNA sequences through the HMG box, activating, inhibiting, or modulating the expression of other genes, playing crucial roles in development. Research shows that Sox genes are involved in sex determination and differentiation, early embryonic development, nervous system development, lens development, cartilage formation, and hematopoiesis.

1. Sox Genes in Sex Determination and Differentiation

Sex determination and differentiation are classical research areas for Sox gene functions. Key genes involved in sex determination include Sry, Sox3, Sox5, Sox6, Sox8, Sox9, and Sox17. The Sry gene, the first cloned gene in the Sox family, has a decisive influence on mammalian testicular development. Additionally, Sox3 and Sox9 genes play important roles in sex determination.

The Sox9 gene is expressed in the early embryonic gonadal ridge cells, promoting the differentiation of testicular support cells. Sox9 protein is primarily cytoplasmic in early embryos but relocates to the nucleus in later stages of testicular development and is not expressed in females, indicating its role in sex determination. The expression level of Sox9 is crucial; a single copy mutation or loss can result in XY females. Mutations in Sox9 may interfere with its DNA binding and bending functions within the HMG box or affect its transcriptional activation outside the HMG box.

In temperature-dependent sex determination animals, such as some turtles, Sox9 is also involved in TSD (Temperature-dependent sex determination). Sox9's role in mammalian male testicular development is similar to that of the Sry gene, acting as a transcription factor to regulate downstream genes. Studies suggest that the Sry gene does not directly regulate testicular development but works in conjunction with Sox9 to achieve its function.

Sox3, the only Sox gene located on the X chromosome and the most homologous to SRY/Sry, does not directly participate in testicular differentiation and development, as shown by the lack of sexual reversal in humans with X chromosome deletions including Sox3. However, Sox3 is widely expressed in mouse embryonic testes, brain, and other adult tissues, and may inhibit Sox9 expression in females while Sry inhibits Sox3 to allow Sox9 expression in males, leading to testis formation.

Sox8 is another key gene in the mammalian testis determination pathway, enhancing Sox9's role in testis formation. Sox8's expression during sex determination in the testis is also significant. Some Sox genes, such as Sox5 and Sox6, are expressed in post-meiotic germ cells in mice, indicating the broad role of Sox genes in sex determination and differentiation.

2. Sox Genes in Nervous System Development

Several Sox family members play crucial roles in nervous system development. Sox1, Sox2, Sox3, and Sox21 are involved in maintaining and differentiating neural stem cells. Sox2 is persistently expressed in neural stem cells and is essential for maintaining their self-renewal ability. Sox2 regulates neural stem cell proliferation and differentiation by activating or inhibiting specific target genes. Additionally, Sox1 plays a significant role in neural tube closure and forebrain development, with mutations causing neural tube closure defects and forebrain malformations in mice.

Sox9 is also crucial for the migration and differentiation of neural crest cells, which are a major source of various cell types during embryonic development, including ganglion cells, pigment cells, and cartilage cells. Sox9's expression level directly influences the fate of neural crest cells.

Furthermore, Sox10 plays a key role in the development of the peripheral nervous system. Sox10 is expressed in neural crest-derived cells of the peripheral nervous system and regulates their proliferation and differentiation. Mutations in Sox10 lead to neurodevelopmental disorders such as Waardenburg syndrome and Hirschsprung disease. These studies highlight the importance of Sox gene family members in nervous system development and related diseases.

3. Sox Genes in Cartilage Development

The role of Sox genes in cartilage development is particularly significant. Sox9 is a key gene in cartilage development, playing a central role in chondrocyte differentiation and cartilage matrix formation. During cartilage development, Sox9 acts with Sox5 and Sox6 to regulate the expression of cartilage matrix genes, such as Collagen type II and Aggrecan. Sox9 promotes cartilage matrix formation by binding to and activating the promoters of these genes. Additionally, Sox9 maintains the chondrocyte phenotype by inhibiting chondrocyte differentiation into osteoblasts.

Sox5 and Sox6 collaborate with Sox9 in cartilage development, assisting in chondrocyte maturation and maintenance. The trimeric complex formed by Sox9, Sox5, and Sox6 plays a crucial role in regulating the expression of cartilage matrix genes. Loss or mutation of Sox9 leads to cartilage development abnormalities, such as cartilage hypoplasia and limited chondrocyte proliferation.

4. Sox Genes in Other Tissue Development

Sox genes also play important roles in the development of other tissues. For instance, Sox18 is crucial for vascular and lymphatic vessel development. Mutations in Sox18 lead to lymphatic edema and other vascular development disorders. Additionally, Sox7 and Sox17 are involved in the development of the endoderm during early embryogenesis, regulating the formation of endoderm-derived organs such as the lungs, liver, and pancreas. Sox genes are also significant in hematopoiesis. Sox4 and Sox18 are critical for the differentiation and proliferation of hematopoietic stem cells. Sox4 is expressed during early differentiation of hematopoietic stem cells and promotes differentiation into specific blood cell lineages by regulating the expression of target genes. Sox18 plays a role in lymphatic vessel formation and lymphocyte differentiation.

Sox genes are critical transcriptional regulators involved in various biological processes, including sex determination, nervous system development, cartilage formation, and tissue development. Recent research has revealed their roles in stem cell maintenance, cancer progression, and genetic disorders. Advances in molecular and structural biology, gene editing technologies, and functional studies continue to enhance our understanding of Sox genes and their applications in medicine and biotechnology.