title: DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development.
abstract: Dipeptidyl-peptidase 6 is an auxiliary subunit of Kv4-mediated A-type K(+) channels that, in addition to enhancing channel surface expression, potently accelerates their kinetics. The dipeptidyl-peptidase 6 gene has been associated with a number of human central nervous system disorders including autism spectrum disorders and schizophrenia. Here we employ knockdown and genetic deletion of dipeptidyl-peptidase 6 to reveal its importance for the formation and stability of dendritic filopodia during early neuronal development. We find that the hippocampal neurons lacking dipeptidyl-peptidase 6 show a sparser dendritic branching pattern along with fewer spines throughout development and into adulthood. In electrophysiological and imaging experiments, we show that these deficits lead to fewer functional synapses and occur independently of the potassium channel subunit Kv4.2. We report that dipeptidyl-peptidase 6 interacts with a filopodia-associated myosin as well as with fibronectin in the extracellular matrix. dipeptidyl-peptidase 6 therefore has an unexpected but important role in cell adhesion and motility, impacting the hippocampal synaptic development and function.
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Ben
authors.initials: B
authors.lastname: Throesch
authors.forename: Faith
authors.initials: F
authors.lastname: Kung
authors.forename: Jameice T
authors.initials: JT
authors.lastname: Decoster
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Berner
authors.forename: Richard E
authors.initials: RE
authors.lastname: Cheney
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rudy
authors.forename: Dax A
authors.initials: DA
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D002448:Cell Adhesion; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000172:deficiency / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D011485:Protein Binding; D011554:Pseudopodia / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D051672:Shal Potassium Channels; C569992:DPP6 protein, mouse; C557320:DPP6 protein, rat; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
references.citation: Scand J Immunol. 2001 Sep;54(3):249-64
references.pmid: 11555388
references.citation: Sci Transl Med. 2010 Sep 15;2(49):49ra68
references.pmid: 20844286
references.citation: Cell Tissue Res. 2001 Sep;305(3):285-98
references.pmid: 11572082
references.citation: J Neurosci Methods. 2010 Jun 30;190(1):71-9
references.pmid: 20438758
references.citation: Neuron. 2007 Jun 21;54(6):933-47
references.pmid: 17582333
references.citation: J Neurosci. 2004 Sep 8;24(36):7903-15
references.pmid: 15356203
references.citation: Neuron. 2003 Feb 6;37(3):449-61
references.pmid: 12575952
references.citation: Nat Cell Biol. 2002 Mar;4(3):246-50
references.pmid: 11854753
references.citation: Exp Cell Res. 2010 Aug 15;316(14):2260-77
references.pmid: 20471381
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12411-6
references.pmid: 16894163
references.citation: J Neurosci. 2006 Feb 8;26(6):1813-22
references.pmid: 16467530
references.citation: Biochem Soc Trans. 2000;28(4):311-39
references.pmid: 10961914
references.citation: J Physiol. 2005 Nov 15;569(Pt 1):41-57
references.pmid: 16141270
references.citation: J Cell Sci. 2011 Nov 15;124(Pt 22):3733-41
references.pmid: 22124140
references.citation: J Biol Chem. 2003 Jul 4;278(27):24600-7
references.pmid: 12716896
references.citation: Adv Exp Med Biol. 2000;477:197-204
references.pmid: 10849747
references.citation: J Cell Biochem. 2002;86(4):726-36
references.pmid: 12210739
references.citation: Annu Rev Neurosci. 2007;30:79-97
references.pmid: 17280523
references.citation: Brain Res. 2006 Jun 13;1094(1):1-12
references.pmid: 16764835
references.citation: J Mol Biol. 2004 Oct 29;343(4):1055-65
references.pmid: 15476821
references.citation: Neuron. 2011 Sep 22;71(6):1102-15
references.pmid: 21943606
references.citation: Mol Cell Neurosci. 2010 Mar;43(3):315-25
references.pmid: 20045463
references.citation: Am J Hum Genet. 2008 Feb;82(2):477-88
references.pmid: 18252227
references.citation: J Gen Physiol. 2006 Dec;128(6):745-53
references.pmid: 17130523
references.citation: J Biochem. 2001 Feb;129(2):289-95
references.pmid: 11173531
references.citation: J Physiol. 2005 Nov 1;568(Pt 3):767-88
references.pmid: 16123112
references.citation: Immunol Today. 1999 Aug;20(8):367-75
references.pmid: 10431157
references.citation: Cancer Res. 2005 Aug 1;65(15):6950-6
references.pmid: 16061680
references.citation: J Biol Chem. 2005 May 13;280(19):18853-61
references.pmid: 15671030
references.citation: J Neurophysiol. 2008 Oct;100(4):1835-47
references.pmid: 18667548
references.citation: J Biol Chem. 2001 Sep 7;276(36):34348-54
references.pmid: 11457842
references.citation: Nat Struct Mol Biol. 2011 Jun 12;18(7):783-8
references.pmid: 21666676
references.citation: Nat Cell Biol. 2004 Jun;6(6):523-31
references.pmid: 15156152
references.citation: J Biol Chem. 2005 Aug 12;280(32):29381-91
references.pmid: 15961399
references.citation: Biochem Biophys Res Commun. 1995 Dec 5;217(1):341-8
references.pmid: 8526932
references.citation: Trends Neurosci. 2010 Jul;33(7):307-16
references.pmid: 20363038
references.citation: J Cell Sci. 2000 Oct;113 Pt 19:3439-51
references.pmid: 10984435
references.citation: J Physiol. 2008 Dec 1;586(23):5609-23
references.pmid: 18845608
references.citation: J Biol Chem. 2012 Mar 16;287(12):9640-50
references.pmid: 22311982