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Forkhead Box D3 (Gene FoxD3) Homo sapiensThe intronless FoxD3 gene (map locus Entrez and HGNC: 1p32-p31; Ensembl: 1p31.3) product, forkhead box D3/HNF3/Genesis/FoxD3, is a 478 amino acids long (47.6 kDa) transcription factor that contains a fork-head DNA binding domain (141-235) and five poly-A regions (from 6 to 14 AA long) in the C-terminal half of the protein. The DNA consensus binding sequence is 5'-A[AT]T[AG]TTTGTTT-3'. FoxD3/HFH2 was initially identified as a member of the winged helix (formerly HNF-3/Forkhed (HFH)) transcription family in embryonal carcinoma, Sutton J, et al. (1996). FoxD3 is expressed in embryonic (ES) stem and embryonic cancer (EC) cells; within the Spemann organizer; in the late-stage gastrula inner cell mass (ICM) (epiblast), Harland R and Gerhart J. (1997); Sutton J, et al. (1996); and in the extra-embryonic tissue (trophectoderm), Tompers DM, et al. (2005). Subsequently, FoxD3 is found in premigrating and migrating neural crest cells, Barembaum M, (2005) and motor-neuron progenitors of the developing spinal cord, Labosky PA and Kaestner KH. (1998); Hromas R, et al. (1999); Dottori M, et al. (2001). Embryonic neural crest cells are the progenitors of the peripheral nervous system and differentiate into peripheral neurons, glia cells, pigment cells and connective tissues of face, neck and heart. They are induced at the junction of the neural plate and embryonic ectoderm to undergo epithelial to mesenchymal transition (EMT) followed by migration into targeted tissues. FoxD3 along with Slug, Zic5 and Soc9 is considered to be a neural crest marker. FoxD3 can act as an activator or repressor of transcription depending upon its cell context and binding partners. FoxD3 is essential for survival of the late stage blastocysts, embryonic stem (ES) and teratocarcinomas (EC) cells, Hanna LA, et al. (2002); Teng L, et al. (2008). It is involved in dorsal mesodermal development within the gastrula. FoxD3 functions as a transcriptional corepressor along with Grg4 (Groucho-related gene-4), Yaklichkin S, et al. (2007) in the Spemann organizer where it induces dorsal mesoderm via expression of Nodal and Nodal-related genes (TGFbeta superfamily), Steiner AB, et al. (2006). In close association with Nanog and OCT4 it anchors an interdependent network of transcription factors that regulate stem cell pluripotency, Pan G, et al. (2006). FoxD3 is involved in early embryonic patterning wherein it participates in the lineage differentiation of neural crest cells. It has been reported to prevent terminal quiescence in primitive neural crest cells by inhibiting p21 expression, Hromas R, et al. (1999). Dottori M, et al. (2001) showed that ectopic expression of FoxD3 in neural tube promoted a neural crest-like phenotype and repression of interneuron differentiation by a Slug and RhoB-independent mechanism. FoxD3 is an upstream regulator of neural crest determination that is required for Slug induction by Zic factors, Sasai N, et al. (2001). FoxD3 is involved in the segregation of neural crest lineage from neuroepithelium and in the repression of melanogenesis, Kos R, et al. (2001). Lister JA, et al. (2006) speculate that Foxd3 may not be essential for induction of neural crest cell identity, but that it may regulate differentiation into specific neural crest cell lineages such as jaw cartilage, peripheral neurons, glia and iridopore pigment cells. FoxD3 repression of neural crest to melanocyte differentiation is blocked by colgate/hdac1 to permit mitfa-dependent melanogenesis to occur, Ignatius MS, et al. (2008). FoxD3 is involved with the delamination of neural crest cells from the neuroepithelium. Sox9 help protect neural crest cells from apoptosis. Slug/Snail, in the presence of Sox 9 induces epithelial mesenchymal transition (EMT) in neural epithelial cells and FoxD3 regulates expression of cell-cell adhesion molecules in support of crest cell migration, Cheung M, et al. (2005). Neural crest tissues are induced by BMP, Wnt and FGF signaling. Wnt signaling in neural crest cells leads to co-activation by Pax3 and Zic1, Sato T, et al. (2005) and subsequent upregulation of Lrig3, Zhao H, et al. (2008) followed by FoxD3 along with slug, Pax3, Msx1 and cadherin 6B signaling during the "premigratory" stages of neural crest development, Taneyhill LA, et al. (2005). Over expression of FoxD3 leads to defective neural crest development, Pohl BS and Knochel W. (2001). FoxD3 is autoregulatory self inhibiting. Sigma offers antibodies and shRNAs useful for the study of FoxD3 gene products. References: Barembaum M, and Bronner-Fraser M. (2005) Early steps in neural crest specification. Semin Cell Dev Biol. 16: 642-646. |
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