SOX2

SRY (sex determining region Y)-box 2, also known as SOX2, is a is_associated_with::transcription factor that is essential for maintaining self-renewal, or is_associated_with::pluripotency, of undifferentiated is_associated_with::embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and is_associated_with::neural stem cells.

Sox2 is a member of the Sox family of is_associated_with::transcription factors, which have been shown to play key roles in many stages of is_associated_with::mammalian development. This is_associated_with::protein family shares highly conserved is_associated_with::DNA binding domains known as HMG (is_associated_with::High-mobility group) box domains containing approximately 80 is_associated_with::amino acids.

Sox2 holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine.

Stem cell pluripotency
LIF (is_associated_with::Leukemia inhibitory factor) signaling, which maintains pluripotency in mouse embryonic stem cells, activates Sox2 downstream of the is_associated_with::JAK-STAT signaling pathway and subsequent activation of Klf4 (a member of the family of is_associated_with::Kruppel-like factors). is_associated_with::Oct-4, Sox2 and is_associated_with::Nanog positively regulate transcription of all pluripotency circuitry proteins in the LIF pathway.

is_associated_with::NPM1, a transcriptional regulator involved in cell proliferation, individually forms complexes with Sox2, Oct4 and is_associated_with::Nanog in embryonic stem cells. These three pluripotency factors contribute to a complex molecular network that regulates a number of genes controlling pluripotency. Sox2 binds to DNA cooperatively with Oct4 at non-palindromic sequences to activate transcription of key pluripotency factors. Surprisingly, regulation of Oct4-Sox2 enhancers can occur without Sox2, likely due to expression of other Sox proteins. However, a group of researchers concluded that the primary role of Sox2 in embryonic stem cells is controlling Oct4 expression, and they both perpetuate their own expression when expressed concurrently.

In an experiment involving mouse embryonic stem cells, it was discovered that Sox2 in conjunction with Oct4, is_associated_with::c-Myc and Klf4 were sufficient for producing is_associated_with::induced pluripotent stem cells. The discovery that expression of only four transcription factors was necessary to induce pluripotency allowed future regenerative medicine research to be conducted considering minor manipulations.

Loss of pluripotency is regulated by hypermethylation of some Sox2 and Oct4 binding sites in male germ cells and post-transcriptional suppression of Sox2 by miR134.

Varying levels of Sox2 affect embryonic stem cells' fate of differentiation. Sox2 inhibits differentiation into the mesendoderm is_associated_with::germ layer and promotes differentiation into neural is_associated_with::ectoderm germ layer. Npm1/Sox2 complexes are sustained when differentiation is induced along the ectodermal lineage, emphasizing an important functional role for Sox2 in ectodermal differentiation.

A study conducted in Milano, Italy showed, through the development of a knockout model, that deficiency of Sox2 results in neural malformities and eventually fetal death, further underlining Sox2’s vital role in embryonic development.

Neural stem cells
In is_associated_with::neurogenesis, Sox2 is expressed throughout developing cells in the is_associated_with::neural tube as well as in proliferating is_associated_with::central nervous system progenitors. However, Sox2 is is_associated_with::downregulated during progenitors' final cell cycle during differentiation when they become post is_associated_with::mitotic. Cells expressing Sox2 are capable of both producing cells identical to themselves and differentiated neural cell types, two necessary hallmarks of stem cells. Proliferation of Sox2+ is_associated_with::neural stem cells can generate neural precursors as well as Sox2+ neural stem cell population.

Induced pluripotency is possible using adult neural stem cells, which express higher levels of Sox2 and c-Myc than embryonic stem cells. Therefore only two exogenous factors, one of which is necessarily Oct4, are sufficient for inducing pluripotent cells from neural stem cells, lessening the complications and risks associated with introducing multiple factors to induce pluripotency.

Eye deformities
Mutations in this gene have been linked with bilateral is_associated_with::anophthalmia, a severe structural eye deformity.

Cancer
In lung development, Sox2 controls the branching morphogenesis of the bronchial tree and differentiation of the epithelium of airways. Overexpression causes an increase in neuroendocrine, gastric/intestinal and basal cells. Under normal conditions, Sox2 is critical for maintaining self-renewal and appropriate proportion of basal cells in adult tracheal epithelium. However, its overexpression gives rise to extensive epithelial is_associated_with::hyperplasia and eventually carcinoma in both developing and adult mouse lungs.

In is_associated_with::squamous cell carcinoma, gene amplifications frequently target the 3q26.3 region. The gene for Sox2 lies within this region, which effectively characterizes Sox2 as an is_associated_with::oncogene. Sox2 is a key upregulated factor in lung squamous cell carcinoma, directing many genes involved in tumor progression. Sox2 overexpression cooperates with loss of Lkb1 expression to promote squamous cell lung cancer in mice. Its overexpression also activates cellular migration and anchorage-independent growth.

Sox2 expression is also found in high is_associated_with::gleason grade is_associated_with::prostate cancer, and promotes is_associated_with::castration-resistant prostate cancer growth.

The ectopic expression of SOX2 may be related to abnormal differentiation of is_associated_with::colorectal cancer cells.

Regulation by thyroid hormone
There are three is_associated_with::thyroid hormone response elements (TREs) in the region upstream of the Sox2 promoter. This region is known as the enhancer region. Studies have suggested that thyroid hormone (T3) controls Sox2 expression via the enhancer region. The expression of TRα1 (thyroid hormone receptor) is increased in proliferating and migrating neural stem cells. It has therefore been suggested that transcriptional repression of Sox2, mediated by the thyroid hormone signaling axis, allows for neural stem cell commitment and migration from the sub-ventricular zone. A deficiency of thyroid hormone, particularly during the first trimester, will lead to abnormal central nervous system development. Further supporting this conclusion is the fact that hypothyroidism during fetal development can result in a variety of neurological deficiencies, including cretinism, characterized by stunted physical development and mental retardation.

Hypothyroidism can arise from a multitude of causes, and is commonly remedied with hormone treatments such as the commonly used Levothyroxine.

Interactions
SOX2 has been shown to interact with is_associated_with::PAX6, NPM1, and is_associated_with::Oct4. SOX2 has been found to cooperatively regulate is_associated_with::Rex1 with is_associated_with::Oct3/4.