The receptors are composed of three extracellular Ig-like domains, a transmembrane SCH727965 in vivo domain, and two intracellular kinase domains (Reuss and von Bohlen und Halbach, 2003). The acid box region between the first and second Ig-like domain determines the ligand specificity. There are also multiple splice variants of the third Ig-like domain resulting in IIIb or IIIc isoforms. The IIIb isoform is expressed predominantly during early development, while the IIIc isoform is expressed predominantly in adulthood. The receptors signal primarily through three main pathways, phospholipase Cγ (PLCγ), mitogen-activated protein kinase (MAPK), and
AKT to influence gene transcription. This signaling is akin to other growth factors; however, the strength of the signaling may vary between growth factors. This is possible, by analogy, since the strength of the signaling can vary between FGF receptor homodimers. For example, FGF ligands in different subfamilies can induce different FGF receptor 1 (FGFR1) homodimer formations and MAPK signaling (Romero-Fernandez et al., 2011). Moreover, there may be differences in kinase activity depending on which molecule triggered the signal (Ditlevsen et al., 2008). Finally, the receptors can interact with other neurotransmitter Screening Library mouse receptors, as will be described in more detail below (see Beyond the FGFs:
Receptor-Interacting Partners). Each of the FGF ligands has a distinct functional substrate level phosphorylation profile. We will focus here on a subset of ligands that are expressed in brain and appear modulated in mood disorders. FGF2, also known as basic fibroblast growth factor, was the first FGF to be cloned in the rat (Kurokawa et al., 1988). It is the prototypical FGF ligand and has been well-characterized for its roles in cell proliferation, differentiation, growth, survival, as well as angiogenesis in various cell models (Ford-Perriss et al., 2001). This ligand is composed of a β trefoil motif and has a basic canyon structure allowing heparin sulfate proteoglycans to bind in a 2:2:2 stoichiometry with the receptors (Reuss
and von Bohlen und Halbach, 2003). FGF2 exists in multiple molecular weight isoforms of which only the lowest molecular weight (18 kDa) is secreted. The higher molecular weight isoforms remain in the nucleus and affect nuclear functioning, such as rRNA transcription. In early brain development, FGF2 is expressed by the neural tube and is involved in neural induction (Ford-Perriss et al., 2001). Later on, FGF2 is expressed in the ventricular region of the developing cortex and the cortical plate. FGF2 is also expressed by neural precursor cells throughout development and promotes the proliferation of neural stem cells (Dono et al., 1998; Vaccarino et al., 1999). Thus, FGF2 knockout mice have alterations in the deep layers of the cortex and the hippocampus compared to wild-type mice (Raballo et al., 2000).