Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal.
Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal.
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DOI：
10.1093/hmg/ddx366
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发表时间：
2018-01-15
影响因子：
3.5
通讯作者：
Fryer JD
中科院分区：
文献类型：
--
作者：
Kang SS;Kurti A;Baker KE;Liu CC;Colonna M;Ulrich JD;Holtzman DM;Bu G;Fryer JD
It is clear that innate immune system status is altered in numerous neurodegenerative diseases. Human genetic studies have demonstrated that triggering receptor expressed in myeloid cells 2 (TREM2) coding variants have a strong association with Alzheimer’s disease (AD) and other neurodegenerative diseases. To more thoroughly understand the impact of TREM2 in vivo, we studied the behavioral and cognitive functions of wild-type (WT) and Trem2−/− (KO) mice during basal conditions and brain function in the context of innate immune stimulation with peripherally administered lipopolysaccharide (LPS). Early markers of neuroinflammation preceded Aif1 and Trem2 upregulation that occurred at later stages (24–48 h post-LPS). We performed a transcriptomic study of these cohorts and found numerous transcripts and pathways that were altered in Trem2−/− mice both at baseline and 48 h after LPS challenge. Importantly, our transcriptome analysis revealed that our Trem2−/− mouse line (Velocigene allele) results in exaggerated Treml1 upregulation. In contrast, aberrantly high Treml1 expression was absent in the Trem2 knockout line generated by the Colonna lab and the Jackson Labs CRISPR/Cas9 Trem2 knockout line. Notably, removal of the floxed neomycin selection cassette ameliorated aberrant Treml1 expression, validating the artifactual nature of Treml1 expression in the original Trem2−/− Velocigene line. Clearly further studies are needed to decipher whether the Treml1 transcriptional artifact is functionally meaningful, but our data indicate that caution is warranted when interpreting functional studies with this particular line. Additionally, our results indicate that other Velocigene alleles or targeting strategies with strong heterologous promoters need to carefully consider downstream genes.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
3.4
作者：
Heppner, FL;Skutella, T;Nitsch, R
通讯作者：
Nitsch, R
DOI：
10.1084/jem.20142322
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jay TR;Miller CM;Cheng PJ;Graham LC;Bemiller S;Broihier ML;Xu G;Margevicius D;Karlo JC;Sousa GL;Cotleur AC;Butovsky O;Bekris L;Staugaitis SM;Leverenz JB;Pimplikar SW;Landreth GE;Howell GR;Ransohoff RM;Lamb BT
通讯作者：
Lamb BT