FOXD3

FOXD3

FOXD3

Protein-coding gene in the species Homo sapiens

Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the FOXD3 gene.[5]

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Function

This gene belongs to the forkhead protein family of transcription factors which is characterized by a DNA-binding forkhead domain. FoxD3 functions as a transcriptional repressor and contains the C-terminal engrailed homology-1 motif (eh1), which provides an interactive surface with a transcriptional co-repressor Grg4 (Groucho-related gene-4).[6]

Stem Cells

Multiple studies have suggested Foxd3 involvement in the transition from naive to primed pluripotent stem cells in embryo development. Previously, Foxd3 was demonstrated to be required in maintaining pluripotency in mouse embryonic stem cells.[7] A recent finding further showed that Foxd3 is necessary as a repressor in the transition from ESC to epiblast-like cells (EpiLC).[8] The study proposed that Foxd3 is associated with inactivation of important naive pluripotency genes by its modification of chromatin structures via recruiting histone demethylases and decreasing the number of activating factors. Another proposed mechanism on the other hand argued that Foxd3 begins nucleosome removal and induction to a "primed" pluripotent state by recruiting Brg1, a nucleosome remodeler, and then acts as a repressor of maximal activation of those enhancers by recruiting histone deacetylases, suggesting a complex mediating function in which enhancers are primed for some future controlled time-point rather than immediate expression.[9] While there is no ambiguity that Foxd3 plays an important role regulating the transition from naive to primed pluripotency state, the two models show a different process. Attempts to reconcile the conclusions of the two studies have further suggested that Foxd3 functions as all of the above.[10]

Neural Crest Cells

FOXD3 plays an important role in the development and differentiation of neural crest cells.[11] Specifically, it is thought that FOXD3 plays an important role in controlling the developmental switch between Schwann Cell Progenitors and Melanocytes.[11]

Clinical significance

Mutations in this gene cause vitiligo.[12]

References

  1. [1]
    GRCh38: Ensembl release 89: ENSG00000187140 – Ensembl, May 2017
  2. [2]
    GRCm38: Ensembl release 89: ENSMUSG00000067261 – Ensembl, May 2017
  3. [3]
    "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. [4]
    "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. [5]
    Hromas R, Moore J, Johnston T, Socha C, Klemsz M (June 1993). "Drosophila forkhead homologues are expressed in a lineage-restricted manner in human hematopoietic cells". Blood. 81 (11): 2854–2859. doi:10.1182/blood.V81.11.2854.2854. PMID 8499623.
  6. [6]
    Yaklichkin S, Steiner AB, Lu Q, Kessler DS (January 2007). "FoxD3 and Grg4 physically interact to repress transcription and induce mesoderm in Xenopus". The Journal of Biological Chemistry. 282 (4): 2548–2557. doi:10.1074/jbc.M607412200. PMC 1780074. PMID 17138566.
  7. [7]
    Hanna LA, Foreman RK, Tarasenko IA, Kessler DS, Labosky PA (October 2002). "Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo". Genes & Development. 16 (20): 2650–2661. doi:10.1101/gad.1020502. PMC 187464. PMID 12381664.
  8. [8]
    Respuela P, Nikolić M, Tan M, Frommolt P, Zhao Y, Wysocka J, Rada-Iglesias A (January 2016). "Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification". Cell Stem Cell. 18 (1): 118–133. doi:10.1016/j.stem.2015.09.010. PMC 5048917. PMID 26748758.
  9. [9]
    Krishnakumar R, Chen AF, Pantovich MG, Danial M, Parchem RJ, Labosky PA, Blelloch R (January 2016). "FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity". Cell Stem Cell. 18 (1): 104–117. doi:10.1016/j.stem.2015.10.003. PMC 4775235. PMID 26748757.
  10. [10]
    Plank-Bazinet JL, Mundell NA (2016). "The paradox of Foxd3: how does it function in pluripotency and differentiation of embryonic stem cells?". Stem Cell Investigation. 3: 73. doi:10.21037/sci.2016.09.20. PMC 5104585. PMID 27868055.
  11. [11]
    Nitzan E, Pfaltzgraff ER, Labosky PA, Kalcheim C (July 2013). "Neural crest and Schwann cell progenitor-derived melanocytes are two spatially segregated populations similarly regulated by Foxd3". Proceedings of the National Academy of Sciences of the United States of America. 110 (31): 12709–12714. Bibcode:2013PNAS..11012709N. doi:10.1073/pnas.1306287110. PMC 3732929. PMID 23858437.
  12. [12]
    Alkhateeb A, Fain PR, Spritz RA (August 2005). "Candidate functional promoter variant in the FOXD3 melanoblast developmental regulator gene in autosomal dominant vitiligo". The Journal of Investigative Dermatology. 125 (2): 388–391. doi:10.1111/j.0022-202X.2005.23822.x. PMID 16098053.

Further reading


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