Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14

Xiao, Maolei; Xu, Lin; Laezza, Fernanda; Yamada, Kelvin A.; Feng, Sheng; Ornitz, David M.

doi:10.1016/j.mcn.2006.11.020

Cited by 75 publications

(91 citation statements)

References 45 publications

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“…However, the absence of observed arrhythmias after TAC in Fgf13 KO mice was unexpected because we had observed flecainide-induced ventricular arrhythmias in Fgf13 KO mice (13)-consistent with FGF13's wellcharacterized role as a positive Na + channel regulator in heart (8,9). Recent analyses of the consequences of FHF KO in brain suggested that FHFs may have roles beyond ion channel regulation, such as regulation of synaptic vesicle release (20) and stabilization of microtubules (21). Thus, we interpreted our unexpected ECG and histological findings, together with the functional preservation observed by echocardiography, to indicate that Fgf13 KO protects against TAC-induced structural remodeling through an unanticipated mechanism independent of Na V 1.5 channel regulation.…”

Section: Fgf13 Ko Hearts Maintain Cardiac Function In Response To Chrsupporting

confidence: 56%

“…Nevertheless, there have been persistent suggestions that FHFs have broader roles, such as regulation of limb (38) and craniofacial development (39), neural differentiation (40), presynaptic neurotransmitter vesicle number (20), and hair growth (41). Although we recently confirmed the role of FGF13 as a regulator of cardiac Na + channels in vivo (13), the complete consequences of Fgf13 ablation on cardiac function have not been investigated.…”

Section: Discussionmentioning

confidence: 99%

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Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na + channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found-even in the context of the expected reduction in Na + channel current-an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling. (1), share a core domain with homology to canonical FGFs, but FHFs are not secreted, do not bind or activate FGF receptors, and do not function as growth factors (2). Instead, FHFs bind directly to voltage-gated Na + channels, modulating channel gating and trafficking (3, 4). Widely expressed in the brain (1), FHFs have been implicated in neurologic diseases such as spinocerebellar ataxia 27, caused by missense mutations in FGF14 that diminish Na + channel current, disrupt channel localization, and impair neuronal excitability (5-7).In addition to their broad distribution in the central nervous system, FHFs are expressed in the mammalian heart (1). Their roles in regulating cardiac function, however, have only been recently investigated. We showed that FGF13, the predominant FHF in rodent heart and a common transcript in human heart (8), directly binds to the C terminus of cardiac Na V 1.5 Na + channels, and thereby regulates current density and conduction velocity by affecting channel gating and surface expression (9). Similarly, mutations that disrupt interaction between Na V 1.5 and FGF12, the major human cardiac FHF, have been linked to lifethreatening arrhythmia syndromes (8, 10). In addition to regulating Na + channels, FHFs can modulate voltage-gated Ca 2+ channels (11, 12). Fgf13 knockdown in adult rodent ventricular cardiomyocytes decreased Ca V 1.2 current density, perturbed Ca V 1.2 localization at the dyad, and thereby affected Ca 2+ -induced Ca 2+ release (11). Because previous studies were conducted in cultured cardiomyocytes, however, the in vivo roles for FHFs in ...

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Section: Fgf13 Ko Hearts Maintain Cardiac Function In Response To Chrsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The iFgf subfamily comprises Fgf11-Fgf14. Fgf12 and Fgf14 knockout mice are viable and have neurological phenotypes (Wang et al, 2002;Xiao et al, 2007;Goldfarb et al, 2007;. Although Fgf11 and Fgf13 knockout mice have not been re-ported, the expression of these genes in the central and peripheral nervous system suggests that these genes will also be found to function in neurodevelopment or neurophysiology.…”

Section: Evolutionary History Of the Mouse Fgf Gene Familymentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

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356

313

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“…The importance of FHFs is underscored by loss-of-function or dominant negative mutations in specific FHFs associated with various neurological disorders, which have been attributed, at least in part, to VGSC dysfunction. Haploinsufficiency for FGF14 or the expression of a dominant negative FGF14 mutant causes spinocerebellar ataxia (SCA27), and Fgf14 −/− mice recapitulate many of the phenotypes observed in patients who have SCA27, including cognitive impairment as well as ataxia (24)(25)(26)(27). In neurons isolated from Fgf14 −/− mice, VGSC currents and excitability are both reduced (23).…”

mentioning

confidence: 99%

Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action

Pablo

Wang

Presby

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Clustering of voltage-gated sodium channels (VGSCs) within the neuronal axon initial segment (AIS) is critical for efficient action potential initiation. Although initially inserted into both somatodendritic and axonal membranes, VGSCs are concentrated within the axon through mechanisms that include preferential axonal targeting and selective somatodendritic endocytosis. How the endocytic machinery specifically targets somatic VGSCs is unknown. Here, using knockdown strategies, we show that noncanonical FGF13 binds directly to VGSCs in hippocampal neurons to limit their somatodendritic surface expression, although exerting little effect on VGSCs within the AIS. In contrast, homologous FGF14, which is highly concentrated in the proximal axon, binds directly to VGSCs to promote their axonal localization. Single-point mutations in FGF13 or FGF14 abrogating VGSC interaction in vitro cannot support these specific functions in neurons. Thus, our data show how the concerted actions of FGF13 and FGF14 regulate the polarized localization of VGSCs that supports efficient action potential initiation.voltage-gated sodium channels | FGF homologous factors | FGF13 | FGF14

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Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14

Cited by 75 publications

References 45 publications

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Functional evolutionary history of the mouse Fgf gene family

Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action

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Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14

Cited by 75 publications

References 45 publications

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Functional evolutionary history of the mouse Fgf gene family

Polarized localization of voltage-gated Na + channels is regulated by concerted FGF13 and FGF14 action

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Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action