Fibroblast Growth Factor 14 Modulates the Neurogenesis of Granule Neurons in the Adult Dentate Gyrus

Abstract

Adult neurogenesis, the production of mature neurons from progenitor cells in the adult mammalian brain, is linked to the etiology of neurodegenerative and psychiatric disorders. However, a thorough understanding of the molecular elements at the base of adult neurogenesis remains elusive. Here, we provide evidence for a previously undescribed function of fibroblast growth factor 14 (FGF14), a brain disease-associated factor that controls neuronal excitability and synaptic plasticity, in regulating adult neurogenesis in the dentate gyrus (DG). We found that FGF14 is dynamically expressed in restricted subtypes of Sex Determining Region Y-Box 2 (Sox2) positive and doublecortin (DCX) positive neural progenitors in the DG. BrdU incorporation studies and confocal imaging revealed that genetic deletion of Fgf14 in Fgf14−/− mice leads to a significant change in the proportion of proliferating, and immature and mature newly born adult granule cells. This results in an increase in the late immature and early mature population of DCX and calretinin (CR) positive neurons. Electrophysiological extracellular field recordings showed reduced minimal threshold response and impaired paired-pulse facilitation at the perforant path to DG inputs in Fgf14−/− compared to Fgf14+/+ mice, supporting disrupted synaptic connectivity as a correlative read-out to impaired neurogenesis. These new insights into the biology of FGF14 in neurogenesis shed light into the signaling pathways associated with disrupted functions in complex brain diseases.

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

“…Compelling evidence indicates that FGF14 is a relevant accessory protein of the Nav channel complex (Hsu et al, 2015; Ali et al, 2016; Alshammari et al, 2016a; Tempia et al, 2015; Shavkunov et al, 2013; Bosch et al, 2015), responsible for action potential initiation and propagation in neurons. In previous studies, we showed that FGF14 forms a complex with neuronal Nav1.6 channel, and this interaction is controlled by S/T kinases (Hsu et al, 2015, 2016; Shavkunov et al, 2013).…”

“…In mice, targeted disruption of FGF14 produces severe ataxia, paroxysmal dystonia, and cognitive impairment (Wang et al, 2002; Wozniak et al, 2007), with neurons that exhibit severe impairments in synaptic transmission and plasticity, and neuronal excitability (Alshammari et al, 2016a,b; Xiao et al, 2007; Wozniak et al, 2007). Significantly, the assembly and trafficking of FGF14 itself is controlled via a GSK–3 dependent signaling pathway that may critically regulate excitability through PPI at the level of the Nav complex (Hsu et al, 2015; Shavkunov et al, 2013).…”

“…Among these, fibroblast growth factor 14 (FGF14) stands out for its specific modulatory roles on neuronal Nav channels. Recent studies highlight the importance of FGF14, a multivalent accessory protein of the Nav channel, in animal as well as human studies (Hsu et al, 2015, 2016; James et al, 2015; Ali et al, 2016; Alshammari et al, 2016a, b, c; Tempia et al, 2015; Ali et al, 2014; Shavkunov et al, 2013). Through direct monomeric binding to the Nav channel C-terminal tail, FGF14 forms a complex with the channel that is required for proper gating, expression and trafficking of the channel to the AIS as well as the control of neuronal excitability (Ali et al, 2014, 2016; Alshammari et al, 2016a; Laezza et al, 2007, 2009; Lou et al, 2005; Wang et al, 2000, 2002; Xiao et al, 2007; Goetz et al, 2009).…”

“…Recent studies highlight the importance of FGF14, a multivalent accessory protein of the Nav channel, in animal as well as human studies (Hsu et al, 2015, 2016; James et al, 2015; Ali et al, 2016; Alshammari et al, 2016a, b, c; Tempia et al, 2015; Ali et al, 2014; Shavkunov et al, 2013). Through direct monomeric binding to the Nav channel C-terminal tail, FGF14 forms a complex with the channel that is required for proper gating, expression and trafficking of the channel to the AIS as well as the control of neuronal excitability (Ali et al, 2014, 2016; Alshammari et al, 2016a; Laezza et al, 2007, 2009; Lou et al, 2005; Wang et al, 2000, 2002; Xiao et al, 2007; Goetz et al, 2009). Using the bioluminescence-based luciferase complementation assay (LCA) (Michnick et al, 2010; Remy & Michnick, 2006; Shavkunov et al, 2012; Villalobos et al, 2007, 2008), a PPI assay that quantitatively measures the complementation of reconstituted FGF14 and Nav1.6 channel complexes, we previously identified glycogen synthase kinase 3 (GSK–3), a multifunctional kinase dysregulated in Alzheimer's, depression and schizophrenia (Emamian, 2012; Jope et al, 2007; Jope & Roh, 2006; Liu et al, 2013; Budni et al, 2012; Scala et al, 2015; Maqbool et al, 2016; Morris & Berk, 2016; Provensi et al, 2016; Avila et al, 2010), as a key modulator of the FGF14:Nav1.6 complex.…”

Adult Neurogenesis in the Songbird: Region-Specific Contributions of New Neurons to Behavioral Plasticity and Stability

“…During both critical periods, numerous factors increase new neuron numbers, 'rescuing' new neurons that would otherwise have died [Shors, 2008;Anderson et al, 2011;Curlik and Shors, 2011;Waddell et al, 2011]. At a mechanistic level, factors that rescue new neurons include neurotrophins such as BDNF [Alvarez-Borda et al, 2004], testosterone and its metabolites [Rasika et al, 1999;Yamamura et al, 2011;Alward et al, 2016] and other growth factors [Alshammari et al, 2015;Joppe et al, 2015;Bakos et al, 2016]. At a behavioral level, neuronal lifespan is influenced by exercise [van Praag et al, 1999;van Praag, 2008], stress [Gould et al, 1997], sleep [Guzman-Marin et al, 2005], social conditions [Lipkind et al, 2002;Alward et al, 2014;Holmes, 2016], learning [Shors et al, 2001[Shors et al, , 2002, and use of the brain region in the absence of learning [Li et al, 2000;Pytte et al, 2010].…”