Developmental Signals - Sox

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Introduction

Mouse (E10.5) Sox10 expression[1]

The SRY (480000) and SOX proteins share a DNA-binding domain known as the HMG box, defined by a 79-amino acid region.


All SOX proteins have a single HMG box and bind linear DNA (transcription factor) in a sequence-specific manner, resulting in the bending of DNA through large angles. Bending causes the DNA helix to open for some distance, which may affect binding and interactions of other transcription factors. SOX1, SOX2 (184429), and SOX3 (313430) show the closest homology to SRY. They share maximum homology within the HMG domain and are expressed mainly in the developing nervous system of the mouse (Collignon et al., 1996). These genes share significant homology outside the HMG box also and are highly conserved throughout their evolution.


Sox2 is first expressed in very early (morula, blastocyst) development, and has also been identified as one of the 4 "Yamanaka Factors" required to generate an induced pluripotential stem cell (iPS cell). It also forms a trimeric complex with OCT4, yet another "Yamanaka Factor".


Mammals have 20 different SOX proteins that can be subdivided into 8 groups: A, B1, B2, C, D, E, F, G, H.

Sox Links: Sox transcription factors cartoon | Image 1 - Preimplantation Mouse | Image 2 - Preimplantation Mouse | Image 3 - Preimplantation Mouse | Sox | Induced Stem Cells | Yamanaka Factors


Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular

Some Recent Findings

  • Sequence alteration in the enhancer contributes to the heterochronic Sox9 expression in marsupial cranial neural crest[2] "Neonates of marsupial mammals are altricial at birth, because their gestation period is relatively short compared to placental mammals. Yet, as they need to travel to the teat from the birth canal, and suckle on the mother's milk, forelimbs and jaws develop significantly early. Previous studies in opossum (Monodelphis domestica), an experimental marsupial model, have revealed that cranial neural crest cells are generated significantly early compared to those in placental mammals, such as mouse, leading to an early development of jaw primordia. We have previously found that Sox9, an important neural crest-specifier gene, is expressed in the future cranial neural crest of the opossum embryonic ectoderm significantly earlier than that in mouse or quail embryos. As Sox9 is essential for neural crest formation in various vertebrates, it seems likely that the heterochronic expression of Sox9 is critical for the early cranial neural crest formation in the marsupial embryos. In this study, we show a marsupial-specific sequence in the Sox9 neural crest enhancer E3. We also reveal that the mouse E3 enhancer is activated in the cranial neural crest cells of quail embryos, that the E3 enhancer with marsupial-specific sequence is activated earlier in the Pax7-expressing neural border prior to the onset of endogenous Sox9 expression, and that a misexpression of cMyb, which is also a transcriptional activator of Pax7, in the neural border can ectopically activate the "marsupialized" enhancer. Thus, we suggest that the modification of the E3 enhancer sequence in the marsupial ancestor would have promoted the early expression of Sox9 in the neural border, facilitating the early formation of the cranial neural crest cells and the subsequent heterochronic development of the jaw primordia."
  • Prenatal Ascertainment of a Fetus With Homozygous Loss of the SOX10 Gene and Phenotypic Correlation by Autopsy Examination [3] "The SOX10 gene plays a vital role in neural crest cell development and migration. Abnormalities in SOX10 are associated with Waardenburg syndrome Types II and IV, and these patients have recognizable clinical features. This case report highlights the first ever reported homozygous loss of function of the SOX10 gene in a human. This deletion is correlated using family history, prenatal ultrasound, microarray analysis of amniotic fluid, and ultimately, a medical autopsy examination to further elucidate phenotypic effects of this genetic variation." (More? neural crest abnormalities)
  • Distinct SoxB1 networks are required for naïve and primed pluripotency[4] "Deletion of Sox2 from mouse embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here, we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from naïve pluripotency." Stem Cells
More recent papers  
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More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Sox Expression | Morula+Sox2 | Blastcyst+Sox2

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells[5] "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." Cartilage Development
  • Just how conserved is vertebrate sex determination?[6] "Sex determination in vertebrate embryos has long been equated with gonadal differentiation into testes or ovaries. This view has been challenged over the years by reports of somatic sexual dimorphisms pre-dating gonadal sex differentiation. ...We illustrate these differences by comparing key sex genes in fishes versus birds and mammals, with emphasis on DM domain genes, the SOX-9AMH pathway in the testis and the FOXL2-Aromatase pathway in the ovary. Such comparisons facilitate the identification of ancient versus derived genes involved in gonadal sex determination. The data indicate that vertebrate sex-determining cascades are not as conserved as once thought."
  • Sox2 is essential for formation of trophectoderm in the preimplantation embryo[7] "In preimplantation mammalian development the transcription factor Sox2 (SRY-related HMG-box gene 2) forms a complex with Oct4 and functions in maintenance of self-renewal of the pluripotent inner cell mass (ICM). ...We conclude that the first essential function of Sox2 in the preimplantation mouse embryo is to facilitate establishment of the trophectoderm lineage. Our findings provide a novel insight into the first differentiation event within the preimplantation embryo, namely the segregation of the ICM and TE lineages."

Human SOX Family

Table - Human Sox Family
Approved
Symbol 		Approved Name Previous Symbols Synonyms Chromosome
SOX1 SRY-box 1 13q34
SOX2 SRY-box 2 3q26.33
SOX3 SRY-box 3 PHP Xq27.1
SOX4 SRY-box 4 6p22.3
SOX5 SRY-box 5 "L-SOX5, MGC35153" 12p12.1
SOX6 SRY-box 6 11p15.3
SOX7 SRY-box 7 8p23.1
SOX8 SRY-box 8 16p13.3
SOX9 SRY-box 9 "CMD1, CMPD1" SRA1 17q24.3
SOX10 SRY-box 10 "DOM, WS4, WS2E" 22q13.1
SOX11 SRY-box 11 2p25.2
SOX12 SRY-box 12 SOX22 20p13
SOX13 SRY-box 13 "Sox-13, ICA12, MGC117216" 1q32.1
SOX14 SRY-box 14 SOX28 3q22.3
SOX15 SRY-box 15 SOX20 "SOX27, SOX26" 17p13.1
SOX17 SRY-box 17 8q11.23
SOX18 SRY-box 18 20q13.33
SOX21 SRY-box 21 SOX25 13q32.1
SOX30 SRY-box 30 5q33.3
SRY sex determining region Y TDF Yp11.2
    Links: Developmental Signals - Sox | OMIM | HGNC | Tbx Family | Bmp Family | Fgf Family | Pax Family | R-spondin Family | Sox Family | Tbx Family


Human SOX Family  
Table - Human Sox Family
Approved
Symbol 		Approved Name Previous Symbols Synonyms Chromosome
SOX1 SRY-box 1 13q34
SOX2 SRY-box 2 3q26.33
SOX3 SRY-box 3 PHP Xq27.1
SOX4 SRY-box 4 6p22.3
SOX5 SRY-box 5 "L-SOX5, MGC35153" 12p12.1
SOX6 SRY-box 6 11p15.3
SOX7 SRY-box 7 8p23.1
SOX8 SRY-box 8 16p13.3
SOX9 SRY-box 9 "CMD1, CMPD1" SRA1 17q24.3
SOX10 SRY-box 10 "DOM, WS4, WS2E" 22q13.1
SOX11 SRY-box 11 2p25.2
SOX12 SRY-box 12 SOX22 20p13
SOX13 SRY-box 13 "Sox-13, ICA12, MGC117216" 1q32.1
SOX14 SRY-box 14 SOX28 3q22.3
SOX15 SRY-box 15 SOX20 "SOX27, SOX26" 17p13.1
SOX17 SRY-box 17 8q11.23
SOX18 SRY-box 18 20q13.33
SOX21 SRY-box 21 SOX25 13q32.1
SOX30 SRY-box 30 5q33.3
SRY sex determining region Y TDF Yp11.2
    Links: Developmental Signals - Sox | OMIM | HGNC | Tbx Family | Bmp Family | Fgf Family | Pax Family | R-spondin Family | Sox Family | Tbx Family

SOX2

In the mouse blastocyst Sox2 forms a complex with Oct4 to maintain self-renewal of the pluripotent inner cell mass (ICM) and is also required for the formation of trophectoderm.[7]

  • Sox2 is first expressed in very early (morula, blastocyst) development.
  • Forms a trimeric transcription complex with OCT4.
  • Gene targets - YES1, FGF4, UTF1 and ZFP206.


Approved
Symbol 		Approved Name Previous Symbols Synonyms Chromosome
SOX2 SRY-box 2 3q26.33
Mouse- embryonic stem cell signaling regulation.jpg

Embryonic stem cell signaling SOX2

SOX9

Adrenal and gonad early development.jpg


SOX9 adrenal and gonad early development[8][9]


Table - Human Sox Family
Approved
Symbol 		Approved Name Previous Symbols Synonyms Chromosome
SOX9 SRY-box 9 "CMD1, CMPD1" SRA1 17q24.3

Early Mouse Expression

Mouse Sox2 expression 01.jpg

Mouse Sox2 expression 02.jpg

Mouse Sox2 expression 03.jpg

Limb Expression

Limb patterning factors 05.jpg

Sox9 expression in E12.5 wild-type mouse embryonic forelimb.[10]

Function

Stem Cells

Sox2

  • one of the 4 "Yamanaka factors" (OCT4, SOX2, KLF4, cMyc) required to make a stem cell.


Links: Stem Cells | Shinya Yamanaka

Genital Development

Sox9

  • regulates sex development.

Cartilage Development

Sox9

  • regulates cartilage development.
  • in chondrogenesis model Sox9 is coexpressed with the gene encoding Col2a1 (type II collagen), the major cartilage matrix protein.
  • up-regulated by fibroblast growth factors (FGFs) in primary chondrocytes.
Links:Cartilage Development

Respiratory Development

Sox2

  • regulates patterning of the anterior foregut into ventral (trachea) and dorsal (esophagus) fates
  • endoderm expression during formation of foregut derivatives
  • declines in regions undergoing lung bud morphogenesis
  • declines in ventral region generating the trachea


Links: Respiratory System Development | StemBook - Specification and patterning of the respiratory system

Rib Development

Mouse E12.5 Sox9 Expression.jpg

Sox9 expression in the Mouse (E12.5) rib primordial.[11]

Neural Development

Sox2 binding sites have been identified in mouse cortical (germinal zone) progenitor cells (this study also identified Pax6 and Lhx2 sites)[12]


Links: Neural System Development | Pax | OMIM Sox2

Hearing Development

Sox2 Lineage tracing of Sox2-expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti[13] "The transcription factor Sox2 is both necessary and sufficient for the generation of sensory regions of the inner ear. ...We find that Sox2-expressing cells in the early otocyst give rise to large numbers of non-sensory structures throughout the inner ear, and that Sox2 only becomes a truly prosensory marker at embryonic day (E)11.5. Our fate map reveals the organ of Corti derives from a central domain on the medial side of the otocyst and shows that a significant amount of the organ of Corti derives from a Sox2-negative population in this region."

Links: Inner Ear Development | Mouse Development | OMIM Sox2

Signaling Pathway

Sox transcription factors cartoon

SOX Developmental Signaling Pathways[14]

OMIM


About OMIM "Online Mendelian Inheritance in Man OMIM is a comprehensive, authoritative, and timely compendium of human genes and genetic phenotypes. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries contain copious links to other genetics resources." OMIM



References

  1. ↑ Paudyal A, Damrau C, Patterson VL, Ermakov A, Formstone C, Lalanne Z, Wells S, Lu X, Norris DP, Dean CH, Henderson DJ & Murdoch JN. (2010). The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear. BMC Dev. Biol. , 10, 87. PMID: 20704721 DOI.
  2. ↑ Wakamatsu Y & Suzuki K. (2019). Sequence alteration in the enhancer contributes to the heterochronic Sox9 expression in marsupial cranial neural crest. Dev. Biol. , 456, 31-39. PMID: 31430446 DOI.
  3. ↑ LeBel DP, Wolff DJ, Batalis NI, Ellingham T, Matics N, Patwardhan SC, Znoyko IY & Schandl CA. (2017). First Report of Prenatal Ascertainment of a Fetus With Homozygous Loss of the SOX10 Gene and Phenotypic Correlation by Autopsy Examination. Pediatr. Dev. Pathol. , , 1093526617744714. PMID: 29216801 DOI.
  4. ↑ Corsinotti A, Wong FC, Tatar T, Szczerbinska I, Halbritter F, Colby D, Gogolok S, Pantier R, Liggat K, Mirfazeli ES, Hall-Ponsele E, Mullin NP, Wilson V & Chambers I. (2017). Distinct SoxB1 networks are required for naïve and primed pluripotency. Elife , 6, . PMID: 29256862 DOI.
  5. ↑ Umeda K, Oda H, Yan Q, Matthias N, Zhao J, Davis BR & Nakayama N. (2015). Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells. Stem Cell Reports , 4, 712-26. PMID: 25818812 DOI.
  6. ↑ Cutting A, Chue J & Smith CA. (2013). Just how conserved is vertebrate sex determination?. Dev. Dyn. , 242, 380-7. PMID: 23390004 DOI.
  7. ↑ 7.0 7.1 Keramari M, Razavi J, Ingman KA, Patsch C, Edenhofer F, Ward CM & Kimber SJ. (2010). Sox2 is essential for formation of trophectoderm in the preimplantation embryo. PLoS ONE , 5, e13952. PMID: 21103067 DOI.
  8. ↑ Val P, Lefrançois-Martinez AM, Veyssière G & Martinez A. (2003). SF-1 a key player in the development and differentiation of steroidogenic tissues. Nucl. Recept. , 1, 8. PMID: 14594453 DOI.
  9. ↑ Penrad-Mobayed M, Perrin C, L'Hôte D, Contremoulins V, Lepesant JA, Boizet-Bonhoure B, Poulat F, Baudin X & Veitia RA. (2018). A role for SOX9 in post-transcriptional processes: insights from the amphibian oocyte. Sci Rep , 8, 7191. PMID: 29740094 DOI.
  10. ↑ Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V & Tabin CJ. (2006). Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. , 2, e216. PMID: 17194222 DOI.
  11. ↑ Plummer NW, Spicher K, Malphurs J, Akiyama H, Abramowitz J, Nürnberg B & Birnbaumer L. (2012). Development of the mammalian axial skeleton requires signaling through the Gα(i) subfamily of heterotrimeric G proteins. Proc. Natl. Acad. Sci. U.S.A. , 109, 21366-71. PMID: 23236180 DOI.
  12. ↑ <pubmed>26721689</pubmed>
  13. ↑ Gu R, Brown RM, Hsu CW, Cai T, Crowder AL, Piazza VG, Vadakkan TJ, Dickinson ME & Groves AK. (2016). Lineage tracing of Sox2-expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti. Dev. Biol. , 414, 72-84. PMID: 27090805 DOI.
  14. ↑ Thu KL, Becker-Santos DD, Radulovich N, Pikor LA, Lam WL & Tsao MS. (2014). SOX15 and other SOX family members are important mediators of tumorigenesis in multiple cancer types. Oncoscience , 1, 326-35. PMID: 25594027 DOI.

Reviews

Lee YH & Saint-Jeannet JP. (2011). Sox9 function in craniofacial development and disease. Genesis , 49, 200-8. PMID: 21309066 DOI.

Kiefer JC. (2007). Back to basics: Sox genes. Dev. Dyn. , 236, 2356-66. PMID: 17584862 DOI.



Search PubMed: Sox

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Cite this page: Hill, M.A. (2023, December 11) Embryology Developmental Signals - Sox. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Sox

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