Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
31
05
2021
accepted:
07
03
2022
revised:
02
05
2022
pubmed:
5
4
2022
medline:
6
5
2022
entrez:
4
4
2022
Statut:
epublish
Résumé
Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.
Identifiants
pubmed: 35377872
doi: 10.1371/journal.pgen.1009638
pii: PGENETICS-D-21-00750
pmc: PMC9060359
doi:
Substances chimiques
Glucose
IY9XDZ35W2
Tti2 protein, rat
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009638Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Am J Hum Genet. 2016 May 5;98(5):909-918
pubmed: 27132593
Nat Rev Genet. 2011 Mar;12(3):204-13
pubmed: 21331091
Genes Brain Behav. 2005 Jun;4(4):209-28
pubmed: 15924554
J Appl Physiol (1985). 2003 Jun;94(6):2510-22
pubmed: 12736193
Neuroinformatics. 2003;1(4):299-308
pubmed: 15043217
J Biol Chem. 2010 Jun 25;285(26):20109-16
pubmed: 20427287
Neurosci Lett. 2010 Oct 4;482(3):235-9
pubmed: 20670674
Diabetologia. 2016 Sep;59(9):1995-2004
pubmed: 27294611
Nature. 2010 Sep 23;467(7314):460-4
pubmed: 20827270
Neurol Neuroimmunol Neuroinflamm. 2020 Aug 19;7(6):
pubmed: 32817202
Prog Neurobiol. 2011 Feb;93(2):182-203
pubmed: 21056618
Methods Mol Biol. 2017;1488:75-120
pubmed: 27933521
Sci Rep. 2020 Jan 23;10(1):1037
pubmed: 31974475
Nat Rev Mol Cell Biol. 2008 Aug;9(8):616-27
pubmed: 18594563
Cell Rep. 2015 Feb 17;10(6):957-967
pubmed: 25683718
Physiol Rev. 2018 Oct 1;98(4):2133-2223
pubmed: 30067154
Genes Dev. 2010 Sep 1;24(17):1939-50
pubmed: 20810650
Nucleic Acids Res. 2019 Jan 8;47(D1):D745-D751
pubmed: 30407521
J Neurosci. 2017 Jan 25;37(4):893-905
pubmed: 28123024
Nat Genet. 2008 May;40(5):516-22
pubmed: 18443588
Front Cell Dev Biol. 2021 Oct 20;9:753175
pubmed: 34746147
Trends Neurosci. 2010 Aug;33(8):345-54
pubmed: 20471112
Nat Methods. 2017 Jul;14(7):687-690
pubmed: 28581496
Pharmacol Res. 2016 Feb;104:156-64
pubmed: 26772814
EMBO J. 2012 Mar 7;31(5):1177-89
pubmed: 22266795
G3 (Bethesda). 2016 Jun 01;6(6):1649-59
pubmed: 27172216
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
pubmed: 12824425
Mol Cell Neurosci. 2003 Sep;24(1):23-40
pubmed: 14550766
PLoS Genet. 2006 Jul;2(7):e114
pubmed: 16848643
Hum Genet. 2018 Jan;137(1):39-44
pubmed: 29164333
Cell. 2013 Jul 18;154(2):452-64
pubmed: 23870131
Genome Res. 2003 Sep;13(9):2082-91
pubmed: 12952877
Neurobiol Learn Mem. 2016 May;131:26-35
pubmed: 26968656
Comp Biochem Physiol B Biochem Mol Biol. 2012 Sep;163(1):26-36
pubmed: 22613819
Development. 2014 Nov;141(21):4076-86
pubmed: 25273085
Genes Cells. 2013 Mar;18(3):161-75
pubmed: 23356578
J Lipid Res. 2012 Jun;53(6):1163-75
pubmed: 22498810
Nat Genet. 2005 Mar;37(3):243-53
pubmed: 15711544
Aging Cell. 2015 Oct;14(5):847-56
pubmed: 26219530
Biostatistics. 2003 Apr;4(2):249-64
pubmed: 12925520
J Neurochem. 2021 Nov;159(3):498-511
pubmed: 34077553
Genes Dev. 2010 Sep 15;24(18):2019-30
pubmed: 20801936
Bioinformatics. 2004 Feb 12;20(3):307-15
pubmed: 14960456
Cell Mol Life Sci. 2014 Jan;71(1):21-42
pubmed: 23543251
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Diabetes. 2010 Jun;59(6):1397-406
pubmed: 20332342
Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20382-7
pubmed: 22159035
Nat Genet. 2015 Nov;47(11):1236-41
pubmed: 26414676
Genetics. 2014 Mar;196(3):911-21
pubmed: 24402375
Physiol Genomics. 2011 Nov 7;43(21):1207-18
pubmed: 21846806
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):883-7
pubmed: 15279773
Cell Rep. 2013 Oct 31;5(2):433-44
pubmed: 24139800
Nat Genet. 2008 Aug;40(8):952-4
pubmed: 18587397
Int J Mol Sci. 2018 Jul 13;19(7):
pubmed: 30011848
PLoS Genet. 2006 Oct 20;2(10):e172
pubmed: 17054398
J Comp Neurol. 1988 Dec 15;278(3):344-52
pubmed: 3216047
Mol Cell Biol. 2008 Jan;28(1):61-70
pubmed: 17967879
J Hum Genet. 2020 Apr;65(4):371-380
pubmed: 31907388
Neuroscience. 2001;107(4):603-13
pubmed: 11720784
Curr Alzheimer Res. 2015;12(8):772-84
pubmed: 26159196
Sci Data. 2016 Mar 15;3:160018
pubmed: 26978244
J Biol Chem. 2009 Sep 18;284(38):25542-52
pubmed: 19633297
Metabolism. 1988 Apr;37(4):303-5
pubmed: 3282146
Methods Mol Biol. 2019;2018:213-231
pubmed: 31228159
Bioinformatics. 2014 Feb 15;30(4):523-30
pubmed: 24336805
BMC Bioinformatics. 2007 Feb 08;8:48
pubmed: 17288599
Nat Neurosci. 2008 Mar;11(3):309-17
pubmed: 18278039
BMC Neurol. 2020 Feb 15;20(1):58
pubmed: 32061250
PLoS One. 2016 Oct 11;11(10):e0164206
pubmed: 27727328
J Am Heart Assoc. 2018 Nov 6;7(21):e009243
pubmed: 30608189
Nat Genet. 2019 Sep;51(9):1339-1348
pubmed: 31427789
Genome Biol. 2019 Oct 25;20(1):222
pubmed: 31653226
Curr Opin Neurobiol. 2017 Feb;42:45-52
pubmed: 27915086
Nucleic Acids Res. 2012 Aug;40(15):e115
pubmed: 22730293
Nat Genet. 2016 Jul;48(7):709-17
pubmed: 27182965
Epidemiol Psychiatr Sci. 2020 Apr 24;29:e118
pubmed: 32326995
J Neurosci. 2012 Oct 24;32(43):15012-26
pubmed: 23100423
Mamm Genome. 2007 Feb;18(2):87-93
pubmed: 17347894
Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210
pubmed: 23847781
J Alzheimers Dis. 2012;30 Suppl 2:S31-75
pubmed: 22561330
EMBO Mol Med. 2011 Dec;3(12):742-54
pubmed: 21984534
Dev Dyn. 2018 Jan;247(1):33-46
pubmed: 28543935
J Neurosci. 2014 Nov 12;34(46):15139-49
pubmed: 25392482
Development. 2003 Jan;130(2):391-9
pubmed: 12466205
Biom J. 2008 Jun;50(3):346-63
pubmed: 18481363
Mol Genet Genomic Med. 2017 Jul 28;5(5):580-584
pubmed: 28944240
J Mol Biol. 2022 Jan 30;434(2):167370
pubmed: 34838521
Clin Exp Hypertens. 2004 May;26(4):287-303
pubmed: 15195685
Nat Commun. 2016 Feb 02;7:10464
pubmed: 26833085
Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):780-5
pubmed: 16407118
Nat Rev Mol Cell Biol. 2008 Apr;9(4):297-308
pubmed: 18285803
Curr Genet. 2018 Oct;64(5):965-970
pubmed: 29470645
Hum Mutat. 2013 Nov;34(11):1472-6
pubmed: 23956177
Diabetologia. 2020 May;63(5):977-986
pubmed: 32016567
Psychoneuroendocrinology. 2018 Jul;93:72-81
pubmed: 29702445
Cell. 2013 Jun 6;153(6):1219-1227
pubmed: 23746839
Nat Genet. 2008 May;40(5):560-6
pubmed: 18443594
Nat Rev Genet. 2003 Nov;4(11):911-6
pubmed: 14634638
Neuroscience. 2000;100(2):251-8
pubmed: 11008165
Nat Genet. 1995 Nov;11(3):241-7
pubmed: 7581446
Nucleic Acids Res. 2020 Jan 8;48(D1):D731-D742
pubmed: 31713623
EBioMedicine. 2020 Sep;59:102954
pubmed: 32818802
Neuroscience. 2000;101(2):357-68
pubmed: 11074159
Genes Dev. 2001 Mar 1;15(5):554-66
pubmed: 11238376
J Neurosci. 2001 Mar 1;21(5):1628-34
pubmed: 11222653
J Neurosci Res. 2001 May 15;64(4):341-7
pubmed: 11340640
Cell Rep. 2021 Jul 6;36(1):109317
pubmed: 34233195
Acta Neurol Scand. 2008 Mar;117(3):205-10
pubmed: 17854417
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Sci Adv. 2020 Aug 26;6(35):eabb1478
pubmed: 32923634
Cell Tissue Res. 2018 Sep;373(3):693-709
pubmed: 29185071
BMC Bioinformatics. 2008 Dec 29;9:559
pubmed: 19114008
Front Neurosci. 2021 Mar 26;15:621076
pubmed: 33841077
Genome Biol. 2012 Apr 27;13(4):r31
pubmed: 22541052
PLoS Biol. 2020 Aug 17;18(8):e3000836
pubmed: 32804946
Neurosci Lett. 2013 Apr 29;541:9-14
pubmed: 23395832
Am J Hum Genet. 2013 Feb 7;92(2):197-209
pubmed: 23375658
Nat Rev Neurosci. 2012 Mar 20;13(4):225-39
pubmed: 22430016
Mol Neurobiol. 2019 May;56(5):3501-3521
pubmed: 30140974
Nat Genet. 2003 Apr;33(4):497-501
pubmed: 12640452
Genetics. 2010 Nov;186(3):767-73
pubmed: 21062962
Nat Rev Mol Cell Biol. 2014 Mar;15(3):155-62
pubmed: 24556838
Clin Genet. 2019 Oct;96(4):354-358
pubmed: 31290144
Cell. 2007 Dec 28;131(7):1248-59
pubmed: 18160036
Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10409-14
pubmed: 9294224
Methods Mol Biol. 2010;597:415-26
pubmed: 20013249
Mol Cell. 2010 Sep 24;39(6):839-50
pubmed: 20864032
J Neurochem. 2002 Feb;80(3):539-47
pubmed: 11905999
Science. 2015 May 8;348(6235):648-60
pubmed: 25954001
J Lipid Res. 2011 Sep;52(9):1672-82
pubmed: 21622629
Physiol Res. 2004;53 Suppl 1:S15-22
pubmed: 15119932
Genome Res. 2010 Jun;20(6):791-803
pubmed: 20430781
Neuroscience. 2010 Dec 29;171(4):973-80
pubmed: 20950672
Front Plant Sci. 2017 Nov 07;8:1723
pubmed: 29163555
Front Genet. 2019 Oct 29;10:1060
pubmed: 31737043
PLoS Genet. 2010 Apr 01;6(4):e1000888
pubmed: 20369019
Neural Plast. 2015;2015:657928
pubmed: 25977822
J Mol Psychiatry. 2015 Jun 04;3(1):6
pubmed: 26110057
Biochim Biophys Acta Biomembr. 2017 Sep;1859(9 Pt B):1573-1582
pubmed: 28315304
Oncogene. 2007 Aug 13;26(37):5358-72
pubmed: 17694078
PLoS Genet. 2011 Apr;7(4):e1002057
pubmed: 21552543
Am J Hum Genet. 2011 Nov 11;89(5):607-18
pubmed: 22077970
Front Cell Neurosci. 2016 Jun 16;10:157
pubmed: 27378854