FOXD3

Last updated
FOXD3
PDB 2hfh EBI.jpg
Identifiers
Aliases FOXD3 , AIS1, Genesis, HFH2, VAMAS2, forkhead box D3
External IDs OMIM: 611539 MGI: 1347473 HomoloGene: 49239 GeneCards: FOXD3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_012183

NM_010425

RefSeq (protein)

NP_036315

NP_034555

Location (UCSC) Chr 1: 63.32 – 63.33 Mb Chr 4: 99.54 – 99.55 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Cellular differentiation</span> Developmental biology

Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. However, metabolic composition does get altered quite dramatically where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having the same genome.

<span class="mw-page-title-main">Oct-4</span> Mammalian protein found in Homo sapiens

Oct-4, also known as POU5F1, is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.

<span class="mw-page-title-main">Homeobox protein NANOG</span> Mammalian protein found in humans

Homeobox protein NANOG(hNanog) is a transcriptional factor that helps embryonic stem cells (ESCs) maintain pluripotency by suppressing cell determination factors. hNanog is encoded in humans by the NANOG gene. Several types of cancer are associated with NANOG.

<span class="mw-page-title-main">FOXP1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.

<span class="mw-page-title-main">FOXO3</span> Protein-coding gene in the species Homo sapiens

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.

<span class="mw-page-title-main">SOX2</span> Transcription factor gene of the SOX family

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

<span class="mw-page-title-main">Forkhead box C1</span> Protein-coding gene in the species Homo sapiens

Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the FOXC1 gene.

<span class="mw-page-title-main">HES1</span> Protein-coding gene in the species Homo sapiens

Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.

<span class="mw-page-title-main">TBX3</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX3 is a protein that in humans is encoded by the TBX3 gene.

<span class="mw-page-title-main">SALL4</span> Protein-coding gene in the species Homo sapiens

Sal-like protein 4(SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.

<span class="mw-page-title-main">Developmental pluripotency associated 2</span> Protein-coding gene in the species Homo sapiens

Developmental pluripotency-associated protein 2 is a protein that in humans is encoded by the DPPA2 gene.

<span class="mw-page-title-main">FOXD4</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein D4 is a protein that in humans is encoded by the FOXD4 gene.

<span class="mw-page-title-main">Rex1</span> Known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells

Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begin to differentiate, Rex1 is severely and abruptly downregulated.

<span class="mw-page-title-main">Forkhead box protein O1</span> Protein

Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

<span class="mw-page-title-main">Cell potency</span> Ability of a cell to differentiate into other cell types

Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency, and finally unipotency.

<span class="mw-page-title-main">FOXJ1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene. It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis. FOXJ1 is expressed in ciliated cells of the lung, choroid plexus, reproductive tract, embryonic kidney and pre-somite embryo stage.

Pioneer factors are transcription factors that can directly bind condensed chromatin. They can have positive and negative effects on transcription and are important in recruiting other transcription factors and histone modification enzymes as well as controlling DNA methylation. They were first discovered in 2002 as factors capable of binding to target sites on nucleosomal DNA in compacted chromatin and endowing competency for gene activity during hepatogenesis. Pioneer factors are involved in initiating cell differentiation and activation of cell-specific genes. This property is observed in histone fold-domain containing transcription factors and other transcription factors that use zinc finger(s) for DNA binding.

<span class="mw-page-title-main">UTF1</span> Protein-coding gene in the species Homo sapiens

Undifferentiated embryonic cell transcription factor 1 is a protein in humans that is encoded by the UTF1 gene. UTF1, first reported in 1998, is expressed in pluripotent cells including embryonic stem cells and embryonic carcinoma cells. Its expression is rapidly reduced upon differentiation. UTF1 protein is localized to the cell nucleus, where it functions to regulate the pluripotent chromatin state and buffer mRNA levels by promoting degradation of mRNA.

<span class="mw-page-title-main">Forkhead box d1</span> Human protein-coding gene

Forkhead box D1 is a protein that in humans is encoded by the FOXD1 gene. Forkhead d1 is a kidney expressed transcription factor maps at the chromosome 5 at position 5q12—q13, identified in Drosophila forkhead protein and mammalian HNF3 transcription factor. The name of was derived from two spiked head structures in the embryos of Drosophila forkhead mutant. It belong to transcription factor family that displays remarkable functional diversity and involved in a wide variety of biological processes. The most commonly used synonyms for Forkhead D1 are, FOX D1, FREAC-4 and BF2.

<span class="mw-page-title-main">F-box protein 15</span>

F-box protein 15 also known as Fbx15 is a protein that in humans is encoded by the FBXO15 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000187140 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000067261 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  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. 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. 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. 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. 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. 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. 1 2 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. 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