Numerous isoforms of Fgf8 reflect its multiple roles in the developing brain

Abstract

Soluble growth factors play an important role in the coordination and integration of cell proliferation, differentiation, fate determination, and morphogenesis during development of multicellular organisms. Fibroblast growth factors (FGFs) are a large family of polypeptide growth factors that are present in organisms ranging from nematodes to humans. RNA alternative splicing of FGFs and their receptors further enhances the complexity of this ligand-receptor system. The mouse Fgf8 gene produces eight splice variants, which encode isoform proteins with different N-termini and distinct receptor-binding affinity and biological activity. In this article, we review the roles of Fgf8 in vertebrate development and summarize the recent findings on the in vivo function of different Fgf8 splice variants. We propose that multiple Fgf8 isoform proteins act in concert to regulate the overall function of Fgf8 and account for the diverse and essential role of Fgf8 during vertebrate development.J. Cell. Physiol. 226: 1722-1726, 2011. ß 2010 Wiley-Liss, Inc. The FGF Family in VertebratesThe first two fibroblast growth factors (FGFs), Fgf1 and Fgf2, were isolated as mitogens for fibroblast from bovine pituitary and brain (Gospodarowicz et al., 1974(Gospodarowicz et al., , 1978Gospodarowicz, 1975;Maciag et al., 1979). Subsequent studies have identified numerous FGFs in various organisms, except for unicellular organisms (Itoh and Ornitz, 2008). In mice and humans, the FGF family is comprised of 22 members, which are grouped into six or seven subfamilies based on similarity in sequence, gene location, and function. Genome sequence analyses suggest that the FGF family may have expanded in two phases by gene duplication during evolution Ornitz, 2004, 2008). The first phase was associated with early metazoan evolution to generate ancestors of 6-7 FGF subfamilies. Subsequently, large-scale genome duplication during the early evolution of vertebrates further expanded the FGF subfamilies to contain 3-4 members. Most of FGF members are secreted proteins with a clear N-terminal signal peptide. FGFs 1, 2, 9, 16, and 20 are secreted proteins though they lack an obvious cleavable N-terminal signal sequence. FGFs 11-14 are intracellular proteins and thus called intracellular FGF (iFGF) (Itoh and Ornitz, 2008). All FGFs contain a conserved core of approximately120 amino acids arranged into a globular domain composed of 12 antiparallel b strands (Eriksson et al., 1991;Zhu et al., 1991). This core domain is important for receptor binding, while the divergent N-and C-termini of FGF can modify the receptor-binding affinity and account for the different biological function of FGF (Mohammadi et al., 2005). In humans and mice, there are four FGF receptors, FGFR1-4, which are receptor tyrosine kinases and contain an extracellular ligand-binding domain with three immunoglobulin domains (I, II, and III), a single-pass transmembrane domain, and intracellular tyrosine kinase domain (Ornitz and Itoh, 2001;Mohammadi et al., 2005). Alternative splicing of FGF...

Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1

“…Young astrocytes have a relatively higher immunoreactivity for all of the proteins mentioned (data not shown). This is also in accord with previous findings showing that HTRA1, FGF8 as well as FGF18 are implicated in brain development [ 36 , 69 , 70 ].…”

Deep Learning/Artificial Intelligence and Blood-Based DNA Epigenomic Prediction of Cerebral Palsy

“…Fibroblast growth factor 8 ( FGF8 ) was another hypo-methylated gene found in our study. The null mutation of this gene in mice confers lethality at an early embryonic stage and leads to malformation of major brain structures [31]. This indicates the importance of normal expression of these genes and suggests a potential pathogenic mechanism by which epigenetic disruption can lead to CP in our study population.…”

Role of fibroblast growth factor 8 in neurite outgrowth from spiral ganglion neurons in vitro

“…In this study, we report a trophic action of FGF8a and FGF8b, two of the four homolog FGF8 splice forms found in human and mouse (Sunmonu et al 2010). In cell cultures of SGN, both isoforms promote neurite outgrowth without affecting neuronal survival.…”

“…Eight FGF8 isoforms have been found in the mouse (FGF8a-h) and four in humans (FGF8a, b, e and f). FGF8a and FGF8b have 100% sequence homology between mouse and human (Sunmonu et al 2010). FGF8 elicits its effects by the activation of four different subtypes of tyrosine kinase FGF receptors, named FGFR1 through FGFR4 (Zhang et al 2006).…”