title: FGF14 localization and organization of the axon initial segment.
abstract: The axon initial segment (AIS) is highly enriched in the structural proteins ankyrin G and βIV-spectrin, the pore-forming (α) subunits of voltage-gated sodium (Nav) channels, and functional Nav channels, and is critical for the initiation of action potentials. We previously reported that FGF14, a member of the intracellular FGF (iFGF) sub-family, is expressed in cerebellar Purkinje neurons and that the targeted inactivation of Fgf14 in mice (Fgf14(-/-)) results in markedly reduced Purkinje neuron excitability. Here, we demonstrate that FGF14 immunoreactivity is high in the AIS of Purkinje neurons and is distributed in a decreasing, proximal to distal, gradient. This pattern is evident early in the postnatal development of Purkinje neurons and is also observed in many other types of central neurons. In (Scn8a(med)) mice, which are deficient in expression of the Nav1.6 α subunit, FGF14 immunoreactivity is markedly increased and expanded in the Purkinje neuron AIS, in parallel with increased expression of the Nav1.1 (Scn1a) α subunit and expanded expression of βIV-spectrin. Although Nav1.1, FGF14, and βIV-spectrin are affected, ankyrin G immunoreactivity at the AIS of Scn8a(med) and wild type (WT) Purkinje neurons was not significantly different. In Fgf14(-/-) Purkinje neurons, βIV-spectrin and ankyrin G immunoreactivity at the AIS were also similar to WT Purkinje neurons, although both the Nav1.1 and Nav1.6 α subunits are modestly, but significantly (p<0.005), reduced within sub-domains of the AIS, changes that may contribute to the reduced excitability of Fgf14(-/-) Purkinje neurons.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maolei
authors.initials: M
authors.lastname: Xiao
authors.forename: Marie K
authors.initials: MK
authors.lastname: Bosch
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011689:Purkinje Cells / Q000378:metabolism; D013049:Spectrin / Q000235:genetics / Q000378:metabolism
chemical_list: D017487:Ankyrins; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse; C491046:Scn8a protein, mouse; C112971:fibroblast growth factor 14; D013049:Spectrin; D005346:Fibroblast Growth Factors
keywords: AIS; Ankyrin G; Axon initial segment; FGF14; Nav; Purkinje neuron; Scn1a; Scn8a; Voltage-gated sodium channel; axon initial segment; fibroblast growth factor 14; iFGF; intracellular fibroblast growth factor; voltage gated sodium channel; βIV-spectrin
references.citation: Mol Cell Neurosci. 2007 Mar;34(3):366-77
references.pmid: 17208450
references.citation: Nat Neurosci. 2006 Sep;9(9):1142-9
references.pmid: 16921370
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):7059-64
references.pmid: 9192691
references.citation: J Cell Biol. 1996 Dec;135(5):1355-67
references.pmid: 8947556
references.citation: J Neurosci. 2007 Oct 10;27(41):11065-74
references.pmid: 17928448
references.citation: Mech Dev. 2000 Feb;90(2):283-7
references.pmid: 10640713
references.citation: Neuron. 2007 Aug 2;55(3):449-63
references.pmid: 17678857
references.citation: Mov Disord. 2006 Mar;21(3):396-401
references.pmid: 16211615
references.citation: J Neurosci. 2004 Jul 28;24(30):6765-75
references.pmid: 15282281
references.citation: J Neurosci. 2003 Mar 15;23(6):2306-13
references.pmid: 12657689
references.citation: J Neurosci. 2003 Jun 15;23(12):4899-912
references.pmid: 12832512
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9850-7
references.pmid: 8790420
references.citation: J Biol Chem. 2011 Jul 8;286(27):24253-63
references.pmid: 21566136
references.citation: Nat Genet. 1995 Aug;10(4):461-5
references.pmid: 7670495
references.citation: Nature. 2010 Jun 24;465(7301):1070-4
references.pmid: 20543823
references.citation: Cell. 2004 Oct 15;119(2):257-72
references.pmid: 15479642
references.citation: Neurobiol Dis. 2009 Jan;33(1):81-8
references.pmid: 18930825
references.citation: Neuron. 2002 Jul 3;35(1):25-38
references.pmid: 12123606
references.citation: J Neurosci Methods. 2000 Dec 15;104(1):45-53
references.pmid: 11163410
references.citation: Nat Neurosci. 2009 Aug;12(8):996-1002
references.pmid: 19633666
references.citation: J Biochem. 2011 Feb;149(2):121-30
references.pmid: 20940169
references.citation: Neurogenetics. 2009 Oct;10(4):371-4
references.pmid: 19471976
references.citation: Hippocampus. 2009 Jul;19(7):677-86
references.pmid: 19156852
references.citation: J Neurosci. 2007 May 30;27(22):5903-14
references.pmid: 17537961
references.citation: J Physiol. 2005 Nov 15;569(Pt 1):179-93
references.pmid: 16166153
references.citation: J Neurosci. 2007 Oct 31;27(44):12033-44
references.pmid: 17978045
references.citation: Genetica. 2004 Sep;122(1):37-45
references.pmid: 15619959
references.citation: Eur J Hum Genet. 2005 Jan;13(1):118-20
references.pmid: 15470364
references.citation: J Neurosci. 2008 Dec 31;28(53):14329-40
references.pmid: 19118165
references.citation: J Biol Chem. 1996 Jul 19;271(29):17576-81
references.pmid: 8663325
references.citation: Neuron. 1997 Oct;19(4):881-91
references.pmid: 9354334
references.citation: J Cell Biol. 2007 Feb 12;176(4):509-19
references.pmid: 17283186
references.citation: J Cell Biol. 2002 Jan 21;156(2):337-48
references.pmid: 11807096
references.citation: J Cell Biol. 2001 Nov 26;155(5):739-46
references.pmid: 11724816
references.citation: Nature. 1994 Jan 6;367(6458):69-72
references.pmid: 8107777
references.citation: Nat Neurosci. 2008 Feb;11(2):178-86
references.pmid: 18204443
references.citation: Mol Cell Neurosci. 2009 Oct;42(2):90-101
references.pmid: 19465131
references.citation: Am J Hum Genet. 2003 Jan;72(1):191-9
references.pmid: 12489043
references.citation: J Cell Biol. 1998 Nov 30;143(5):1295-304
references.pmid: 9832557
references.citation: J Neurosci. 2006 Jul 5;26(27):7172-80
references.pmid: 16822974
references.citation: J Cell Biol. 2007 Aug 27;178(5):875-86
references.pmid: 17709431
references.citation: Mol Cell Neurosci. 2008 Oct;39(2):180-92
references.pmid: 18621130
references.citation: J Comp Neurol. 2007 Jan 10;500(2):339-52
references.pmid: 17111377
references.citation: Neuroscientist. 2009 Dec;15(6):651-68
references.pmid: 20007821