Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors

Lin Luo; Mateusz C. Ambrozkiewicz; Fritz Benseler; Cui Chen; Emilie Dumontier; Susanne Falkner; Elisabetta Furlanis; Andrea M. Gomez; Naosuke Hoshina; Wei Hsiang Huang; Mary Anne Hutchison; Yu Itoh-Maruoka; Laura A. Lavery; Wei Li; Tomohiko Maruo; Junko Motohashi; Emily Ling Lin Pai; Kenneth A. Pelkey; Ariane Pereira; Thomas Philips; Jennifer L. Sinclair; Jeff A. Stogsdill; Lisa Traunmüller; Jiexin Wang; Joke Wortel; Wenjia You; Nashat Abumaria; Kevin T. Beier; Nils Brose; Harold A. Burgess; Constance L. Cepko; Jean François Cloutier; Cagla Eroglu; Sandra Goebbels; Pascal S. Kaeser; Jeremy N. Kay; Wei Lu; Liqun Luo; Kenji Mandai; Chris J. McBain; Klaus Armin Nave; Marco A.M. Prado; Vania F. Prado; Jeffrey Rothstein; John L.R. Rubenstein; Gesine Saher; Kenji Sakimura; Joshua R. Sanes; Peter Scheiffele; Yoshimi Takai; Hisashi Umemori; Matthijs Verhage; Michisuke Yuzaki; Huda Yahya Zoghbi; Hiroshi Kawabe; Ann Marie Craig

doi:10.1016/j.neuron.2020.01.008

Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors

Lin Luo, Mateusz C. Ambrozkiewicz, Fritz Benseler, Cui Chen, Emilie Dumontier, Susanne Falkner, Elisabetta Furlanis, Andrea M. Gomez, Naosuke Hoshina, Wei Hsiang Huang, Mary Anne Hutchison, Yu Itoh-Maruoka, Laura A. Lavery, Wei Li, Tomohiko Maruo, Junko Motohashi, Emily Ling Lin Pai, Kenneth A. Pelkey, Ariane Pereira, Thomas PhilipsJennifer L. Sinclair, Jeff A. Stogsdill, Lisa Traunmüller, Jiexin Wang, Joke Wortel, Wenjia You, Nashat Abumaria, Kevin T. Beier, Nils Brose, Harold A. Burgess, Constance L. Cepko, Jean François Cloutier, Cagla Eroglu, Sandra Goebbels, Pascal S. Kaeser, Jeremy N. Kay, Wei Lu, Liqun Luo, Kenji Mandai, Chris J. McBain, Klaus Armin Nave, Marco A.M. Prado, Vania F. Prado, Jeffrey Rothstein, John L.R. Rubenstein, Gesine Saher, Kenji Sakimura, Joshua R. Sanes, Peter Scheiffele, Yoshimi Takai, Hisashi Umemori, Matthijs Verhage, Michisuke Yuzaki, Huda Yahya Zoghbi, Hiroshi Kawabe^*, Ann Marie Craig

^*Corresponding author for this work

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Abstract

Luo et al. report variable rates of germline recombination in commonly used mouse Cre driver lines, influenced by sex of Cre-carrying parents and target loci. Guidelines are provided to optimize cell-type-specific recombination in genetically targeted organisms expressing site-specific recombinases.

Original language	English
Pages (from-to)	37-65.e5
Number of pages	35
Journal	Neuron
Volume	106
Issue number	1
Early online date	5 Feb 2020
DOIs	https://doi.org/10.1016/j.neuron.2020.01.008
Publication status	Published - 8 Apr 2020

Funding

We thank Dr. Cynthia Smith from the Jackson Laboratory for her open acceptance of our data on the MGI database. We thank Dr. Timothy Murphy for his kind gift of the Ai32 mouse line. We thank Drs. Elizabeth M. Simpson, Sören Lukassen, and the University of British Columbia Dynamic Brain Circuits Cluster for discussion. Work by Lin Luo and A.M.C. was supported by Canadian Institutes of Health Research ( FDN-143206 ) and Simons Foundation Autism Research Initiative ( SFARI 608066 ). Work by M.C.A. and H.K. was supported by German Research Foundation ( SPP1365/KA3423/1-1 and KA3423/3-1 ) and Japan Society for the Promotion of Science (JSPS) KAKENHI grant number 15K21769 . Work by N.B. and F.B. was supported by European Research Council (ERC) Advanced Grant SYNPRIME and the German Research Foundation SFB 1286/A9 awards to N.B. Work by C.C., W. Li, and N.A. was supported by the Natural Science Foundation of China grant ( 81573408 ), Fudan University-Shanghai Institute of Materia Medica Chinese Academy of Science joint grant ( FU-SIMM20174015 ), and the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01 ). Work by J.L.S. and H.A.B. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development . Work by K.T.B. was supported by National Institutes of Health (NIH) grant F32 DA038913 and NIH grant K99/R00 DA041445 . Work by W.Y. and C.C. was supported by a Howard Hughes Medical Institute (HHMI) salary awarded to C.C. Work by E.D. and J.-F.C. was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada (NSERC) . Work by J.A.S. and C.E. was supported by NIH grants RO1DA031833 and F31NS092419 . Work by J. Wang and P.S.K. was supported by NIH grants R01NS083898 , R01NS103484 , and R01MH113349 . Work by A.P. and J.N.K. was supported by NIH grants EY024694 to J.N.K. and EY5722 to Duke University. Work by M.A.H. and W. Lu was supported by National Institute of Neurological Disorders and Stroke (NINDS) and NIH Intramural Research Program . Work by W.-H.H. and Liqun Luo was supported by HHMI , SFARI Research Award 345098, and NIH grant R01NS050580 to Liqun Luo and NIH grant 5K99HD092545-02 to W.-H.H. Work by T.M. and K.M. was supported by Japan's Ministry of Education, Culture, Sports, Science and Technology KAKENHI grant 16H06463 and JPSP KAKENHI grant 18K06503 . Work by K.A.P. and C.J.M. was supported by a Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Award . Work by S.G., G.S., and K.-A.N. was supported by ERC Advanced Grants AxoGLIA and MyeliNANO , the German Research Foundation ( SPP1757 ), and the Max Planck Society . Work by M.A.M.P. and V.F.P. was supported by Canadian Institute of Health Research grants MOP136930 , MOP89919 , PJT 162431 , and PJT 159781 and NSERC grant 06577-2018 RGPIN . Work by E.L.-L.P. and J.L.R.R. was supported by NIH NINDS grant R01 NS099099 , National Institute of Mental Health (NIMH) grant R01 MH081880 , and NIMH grant R01 MH049428 . Work by J.R.S. was supported by NIH R37NS029169 . Work by S.F., E.F., A.M.G., L.T., and P.S. was supported by ERC Advanced Grant SPLICECODE; Swiss National Science Foundation to P.S. and European Molecular Biology Organization EMBO ALTF-70-2015 and aALTF-760-2016 to A.M.G. Work by Y.T. was supported by JPSP KAKENHI grant 26251013 . Work by H.U. was supported by NIH R01DA042744 , R01MH111647 , R01NS092578 , and SFARI grants. Work by J. Wortel and M.V. was supported by an ERC Advanced Grant ( 322966 ) of the European Union. Work by J.M. and M.Y. was supported by Japan Science and Technology Agency ( JPMJCR1854 ) and KAKENHI ( 16H06461 and 15H05772 ). Work by L.A.L. and H.Y.Z. was supported by NIH/NINDS grant 5R01NS057819-13 as well as HHMI to H.Y.Z.

Funders	Funder number
Fudan University-Shanghai Institute of Materia Medica Chinese Academy of Science	FU-SIMM20174015
JPSP	18K06503, SPP1757
University of British Columbia Dynamic Brain Circuits Cluster
National Institutes of Health	K99/R00 DA041445
Howard Hughes Medical Institute
National Institute of Mental Health	R01MH111647, R01 MH081880, R01 MH049428
National Institute on Drug Abuse	F32DA038913
National Institute of Neurological Disorders and Stroke	R01NS050580, R01NS083898, R37NS029169, R01NS092578, 345098, 5K99HD092545-02, F31NS092419, R01 NS099099, R01NS103484
European Molecular Biology Organization	ALTF-70-2015, 26251013, R01DA042744, 322966
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Simons Foundation Autism Research Initiative	608066
Canadian Institutes of Health Research	06577-2018 RGPIN, MOP89919, PJT 162431, PJT 159781, MOP136930, FDN-143206
Natural Sciences and Engineering Research Council of Canada	R01MH113349, EY5722, RO1DA031833, EY024694
European Commission
European Research Council	SFB 1286/A9
Deutsche Forschungsgemeinschaft	SPP1365/KA3423/1-1, KA3423/3-1
Japan Society for the Promotion of Science	15K21769
Ministry of Education, Culture, Sports, Science and Technology	16H06463
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
National Natural Science Foundation of China	81573408
Japan Science and Technology Agency	16H06461, 5R01NS057819-13, 15H05772, JPMJCR1854
Science and Technology Commission of Shanghai Municipality	2018SHZDZX01
Max-Planck-Gesellschaft

Keywords

conditional gene targeting
conditional knockin
conditional knockout
conditional reporter
Cre-lox
germline recombination
molecular genetics
mosaic recombination
parental sex bias
site-specific recombinase

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10.1016/j.neuron.2020.01.008

Optimizing Nervous System-Specific Gene Targeting with Cre Driver LinesFinal published version, 6.3 MBLicence: Article 25fa Dutch Copyright Act

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Luo, L., Ambrozkiewicz, M. C., Benseler, F., Chen, C., Dumontier, E., Falkner, S., Furlanis, E., Gomez, A. M., Hoshina, N., Huang, W. H., Hutchison, M. A., Itoh-Maruoka, Y., Lavery, L. A., Li, W., Maruo, T., Motohashi, J., Pai, E. L. L., Pelkey, K. A., Pereira, A., ... Craig, A. M. (2020). Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors. Neuron, 106(1), 37-65.e5. https://doi.org/10.1016/j.neuron.2020.01.008

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abstract = "Luo et al. report variable rates of germline recombination in commonly used mouse Cre driver lines, influenced by sex of Cre-carrying parents and target loci. Guidelines are provided to optimize cell-type-specific recombination in genetically targeted organisms expressing site-specific recombinases.",

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Luo, L, Ambrozkiewicz, MC, Benseler, F, Chen, C, Dumontier, E, Falkner, S, Furlanis, E, Gomez, AM, Hoshina, N, Huang, WH, Hutchison, MA, Itoh-Maruoka, Y, Lavery, LA, Li, W, Maruo, T, Motohashi, J, Pai, ELL, Pelkey, KA, Pereira, A, Philips, T, Sinclair, JL, Stogsdill, JA, Traunmüller, L, Wang, J, Wortel, J, You, W, Abumaria, N, Beier, KT, Brose, N, Burgess, HA, Cepko, CL, Cloutier, JF, Eroglu, C, Goebbels, S, Kaeser, PS, Kay, JN, Lu, W, Luo, L, Mandai, K, McBain, CJ, Nave, KA, Prado, MAM, Prado, VF, Rothstein, J, Rubenstein, JLR, Saher, G, Sakimura, K, Sanes, JR, Scheiffele, P, Takai, Y, Umemori, H, Verhage, M, Yuzaki, M, Zoghbi, HY, Kawabe, H & Craig, AM 2020, 'Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors', Neuron, vol. 106, no. 1, pp. 37-65.e5. https://doi.org/10.1016/j.neuron.2020.01.008

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AU - Chen, Cui

AU - Dumontier, Emilie

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AU - Furlanis, Elisabetta

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AU - Kay, Jeremy N.

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AU - Luo, Liqun

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AU - Umemori, Hisashi

AU - Verhage, Matthijs

AU - Yuzaki, Michisuke

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AU - Kawabe, Hiroshi

AU - Craig, Ann Marie

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KW - conditional knockin

KW - conditional knockout

KW - conditional reporter

KW - Cre-lox

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Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors

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