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Fibroblast Growth Factor 8The human FGF8 (map locus: Entrez: 10q24; Ensembl: 10q24.32; HGNC 10q25-q26) gene yields four isoforms by alternative splicing; FGF-8A, FGF-8B, FGF-8E and FGF-8F. These isoforms share a 22 AA (1-22) signal sequence that is cleaved to yield the mature proteins. Precursor fibroblast growth factor-8E is a 233 AA (26.5 kDa) protein that yields mature 211 AA (23-233) FGF-8E. PreFGF-8A, preFGF-8B and preFGF-8F are 204 AA, 215 AA and 244 AA long, respectively. These isoforms share a common carboxyl region, but have variable amino termini, Gemel J, et al. (1996). FGF-8A and FGF-8B are highly conserved spliceforms (isoforms). FGF-8B has a more potent inductive activity due to its higher FGF receptor affinity. FGF-8B is present in pre-gastrulation embryos and supports proper alignment of the anterior-posterior (A-P) axis with the uterine axes and shape of the embryo, Guo Q and Li JY. (2007). FGF-8B is the primary form involved in mesoderm development and together with FGF-2A regulates midbrain/hindbrain and spinal cord development, Fletcher RB, et al. (2006). The isthmic organizer (IO) is a secondary signaling center located at the midbrain/hindbrain boundary (MHB) that controls the development of the rostral hindbrain (metencephalon) and the caudal midbrain (mesencephalon) that give rise to the cerebellum and tectum, respectively, Nakamura H and Watanabe Y, (2005). FGF-8 isoforms A and B are expressed in the midbrain/hindbrain neuroepithelium (IO) and provide organizing signals for brain regionalization, Crossley PH and Martin GR, (1995). Pax2 is necessary and sufficient for induction of FGF8 at the mid/hindbrain boundary; however En1, Otx2, Gbx2, Grg4, Wnt1 and Wnt4 refine FGF8 expression through opposing effects on Pax2, Ye W, et al. (2001). The expression of FGF8 at the IO requires Xiro1, Glavic A, et al. (2002). FGF-8B is an inducer of cerebellum development and FGF-8A promotes midbrain development. Regionalization of the midbrain-hindbrain domain involves Fgf8 expression in the context of Gbx2 and Otx2 gene expression, Hidalgo-Sánchez M, et al. (1999) wherein the expression of FGF8 in the isthmic organizer is regulated by the overlapping expression of Otx2 and Gbx2. FGF-8B represses Otx2, but upregulates Gbx2 and Irx1 in the cerebellum, Sato T, et al. (2001). FGF8 stabilizes Gbx2 expression and induces the En1, En2, Pax2, Pax5 and Wnt1 genes, Liu A. et al.(1999) and Garda AL, et al. (2001). FGF-8B induces rhombomere 1 gene Gbx2 expression that supports cerebellar development and represses Otx2 expression. The differential effects of 8A and 8B on region development may relate to receptor affinity. The activity of FGF-8 at the MHB is also modulated by FGF17b and FGF18, Liu, et al. (2003). The effect of FGF8 in brain regionalization is modulated by other genes. In the forebrain, Six3 supports the expression of Bf1, a gene essential for the telencephalon and eye development, and Nkx2.1, which is required for development of the hypothalamus, whereas Irx3 supports the expression of En2 and Nkx6.1. Six3 and Irx can mutually repress their expression, Kobayashi D, et al. (2002). FGF8 is involved in the induction, initiation, and maintenance of chick limb development, Crossley PH, et al. (1996b). Recent studies have demonstrated that FGF4 and FGF8 in the apical ectodermal ridge (AER) are required to maintain cell survival in the limb bud mesenchyme, Boulet AM, et al. (2004). FGF8 is expressed throughout the AER and precedes expression of FGF4, FGF9 and FGF17 and it is the only AER-FGF necessary for normal limb development, Lewandoski M, et al (2000). In addition to supporting cell survival, FGF8 directs proximal-distal patterning in the developing limb, Mariani FV, et al. (2008). Sigma offers antibodies and shRNAs useful for the study of FGF8 gene products.. References:
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