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Event: 2329

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Sine oculis homeobox 1 gene expression, increased

Short name

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SIX1 gene expression, increased

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
precursor cell

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
gene expression	homeobox protein SIX1	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Early-life ER agonism and endometrial adenosquamous carcinoma via SIX1 expression	KeyEvent	Travis Karschnik (send email)	Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Sus scrofa	Sus scrofa	High	NCBI
Gallus gallus	Gallus gallus	High	NCBI
Xenopus sp.	Xenopus sp.	High	NCBI
Danio rerio	Danio rerio	High	NCBI
Mus musculus	Mus musculus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Embryo	High
Adult	High
Fetal	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The sine oculis homeobox homolog (SIX1) gene encodes a transcription factor that plays a central role during organ and tissue formation during embryonic development. SIX1 expression occurs at a high level during this period and can be found in progenitor cells in muscle, organ, and epithelial tissues (Suen et al., 2019 and Xu et al., 2003). In normal adults, SIX1 expression is minimal or non-existent and generally localized in specific tissues like skeletal muscle satellite cells (Madani 2022). SIX1 has been shown to be upregulated in adults with various tissue and organ cancers e.g., breast, cervical, uterine, liver, colon, lung etc… (McCoy et al., 2009 and Balçık-Erçin et al., 2023).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Quantitative PCR and RNA sequencing for general expression.

In situ hybridization to measure localiztion of SIX1 mRNA in tissue.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic Applicability

This gene is highly conserved among vertebrates for its role in tissue development. Orthologs and SIX family genes are conserved in some bilaterian invertebrates for the same reason. Measurements of SIX1 transcript levels have been made across vertebrates broadly including rodents, fish, birds, and amphibians. SIX1 homologs and SIX-family transcription factors are expressed and have been measured in in invertebrates as well, e.g., C. elegans, D. melanogaster (Cheyette et al., 1994 and Vidal et al., 2022). SeqAPASS results for taxaonomc conservation is attached for SIX1a (NP_001009904.1), SIX1b (NP_996978.1), and SIX1 (NP_005973.1) as SIX1 SeqAPASS.csv.

Lifestage Applicability

Specifically in mice, chickens, Xenopus, and Danio sp. SIX1 has been measured during embyogenesis and, when re-activated in adults under certain conditions. Expression of this gene is not sex specific.

Sex Applicability

Expression of this gene is not sex specific.

References

List of the literature that was cited for this KE description. More help

Balçık-Erçin, P., Aysan, A., Salık, N., & Erciyas, E. (2023). SIX1 Downregulation Suppresses Self-renewal Capacity and THY1 Expression in Hepatocellular Carcinoma and SIX1 Dominate the Survival in Liver Cancer. The Turkish Journal of Gastroenterology, 34(8), 881.

Bricaud, O., & Collazo, A. (2006). The transcription factor six1 inhibits neuronal and promotes hair cell fate in the developing zebrafish (Danio rerio) inner ear. Journal of Neuroscience, 26(41), 10438-10451.

Cheyette, B. N., Green, P. J., Martin, K., Garren, H., Hartenstein, V., & Zipursky, S. L. (1994). The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron, 12(5), 977-996.

Coletta, R. D., McCoy, E. L., Burns, V., Kawakami, K., McManaman, J. L., Wysolmerski, J. J., & Ford, H. L. (2010). Characterization of the Six1 homeobox gene in normal mammary gland morphogenesis. BMC developmental biology, 10(1), 4.

Madani, R. (2022). The regulation of myogenesis by SIX homeoproteins and the role of SIX-1 cofactor, LRRFIP2, in satellite cells during skeletal muscle regeneration (Doctoral dissertation, Université Paris Cité).

McCoy, E. L., Iwanaga, R., Jedlicka, P., Abbey, N. S., Chodosh, L. A., Heichman, K. A., ... & Ford, H. L. (2009). Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. The Journal of clinical investigation, 119(9), 2663-2677.

Suen, A. A., Jefferson, W. N., Wood, C. E., & Williams, C. J. (2019). SIX1 regulates aberrant endometrial epithelial cell differentiation and cancer latency following developmental estrogenic chemical exposure. Molecular Cancer Research, 17(12), 2369-2382.

Vidal, B., Gulez, B., Cao, W. X., Leyva-Díaz, E., Reilly, M. B., Tekieli, T., & Hobert, O. (2022). The enteric nervous system of the C. elegans pharynx is specified by the Sine oculis-like homeobox gene ceh-34. Elife, 11, e76003.

Wu, W., Huang, R., Wu, Q., Li, P., Chen, J., Li, B., & Liu, H. (2014). The role of Six1 in the genesis of muscle cell and skeletal muscle development. International journal of biological sciences, 10(9), 983.

Xu, P. X., Zheng, W., Huang, L., Maire, P., Laclef, C., & Silvius, D. (2003). Six1 is required for the early organogenesis of mammalian kidney.