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 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

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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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. Lin Luo, H.K. and A.M.C. conceived the project. All authors contributed unpublished data to Tables 1 or 2. Lin Luo and A.M.C. generated the figures, collated and analyzed the data, and wrote the manuscript with input from all authors. The authors declare no competing interests. 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
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Max-Planck-Gesellschaft
National Institutes of Health
University of British Columbia Dynamic Brain Circuits Cluster
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Howard Hughes Medical Institute
Ministry of Education, Culture, Sports, Science and Technology
National Institute of Neurological Disorders and Stroke	R01NS050580, R01NS083898, R01NS102237, R37NS029169, ZIANS003136, R01NS092578, 345098, R01NS057819, F31NS092419, R01NS050835, R01NS103484, R01NS099099
National Institute of Mental Health	R01MH113349, R01MH111647, R01MH081880, R01 MH049428
National Institute on Drug Abuse	F32DA038913, R01DA042744, R01DA031833, R00DA041445
National Eye Institute	P30EY012196, R01EY024694, P30EY005722
Japan Society for the Promotion of Science	15K21769, 16H06463
National Institute of Child Health and Human Development	ZIAHD008884, K99HD092545, ZIAHD001205, P50HD103555
Horizon 2020 Framework Programme	694584, 670283
Fudan University-Shanghai Institute of Materia Medica Chinese Academy of Science	FU-SIMM20174015
Canadian Institutes of Health Research	06577-2018 RGPIN, PJT 162431, MOP89919, PJT 159781, MOP136930, FDN-143206
JPSP	18K06503, SPP1757
Simons Foundation Autism Research Initiative	608066
European Molecular Biology Organization	ALTF-70-2015, R01NS092578, 26251013, R01MH111647, R01DA042744
Natural Sciences and Engineering Research Council of Canada	R01MH113349, R01NS083898, F31NS092419, RO1DA031833, EY024694, R01NS103484
European Commission	322966
National Natural Science Foundation of China	81573408
European Research Council	SFB 1286/A9
Japan Science and Technology Agency	16H06461, 5R01NS057819-13, 15H05772, JPMJCR1854
Deutsche Forschungsgemeinschaft	SPP1365/KA3423/1-1, KA3423/3-1
Science and Technology Commission of Shanghai Municipality	2018SHZDZX01

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

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.",

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

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

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doi = "10.1016/j.neuron.2020.01.008",

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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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T2 - Prevalence of Germline Recombination and Influencing Factors

AU - Luo, Lin

AU - Ambrozkiewicz, Mateusz C.

AU - Benseler, Fritz

AU - Chen, Cui

AU - Dumontier, Emilie

AU - Falkner, Susanne

AU - Furlanis, Elisabetta

AU - Gomez, Andrea M.

AU - Hoshina, Naosuke

AU - Huang, Wei Hsiang

AU - Hutchison, Mary Anne

AU - Itoh-Maruoka, Yu

AU - Lavery, Laura A.

AU - Li, Wei

AU - Maruo, Tomohiko

AU - Motohashi, Junko

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AU - Pelkey, Kenneth A.

AU - Pereira, Ariane

AU - Philips, Thomas

AU - Sinclair, Jennifer L.

AU - Stogsdill, Jeff A.

AU - Traunmüller, Lisa

AU - Wang, Jiexin

AU - Wortel, Joke

AU - You, Wenjia

AU - Abumaria, Nashat

AU - Beier, Kevin T.

AU - Brose, Nils

AU - Burgess, Harold A.

AU - Cepko, Constance L.

AU - Cloutier, Jean François

AU - Eroglu, Cagla

AU - Goebbels, Sandra

AU - Kaeser, Pascal S.

AU - Kay, Jeremy N.

AU - Lu, Wei

AU - Luo, Liqun

AU - Mandai, Kenji

AU - McBain, Chris J.

AU - Nave, Klaus Armin

AU - Prado, Marco A.M.

AU - Prado, Vania F.

AU - Rothstein, Jeffrey

AU - Rubenstein, John L.R.

AU - Saher, Gesine

AU - Sakimura, Kenji

AU - Sanes, Joshua R.

AU - Scheiffele, Peter

AU - Takai, Yoshimi

AU - Umemori, Hisashi

AU - Verhage, Matthijs

AU - Yuzaki, Michisuke

AU - Zoghbi, Huda Yahya

AU - Kawabe, Hiroshi

AU - Craig, Ann Marie

PY - 2020/4/8

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AB - 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.

KW - conditional gene targeting

KW - conditional knockin

KW - conditional knockout

KW - conditional reporter

KW - Cre-lox

KW - germline recombination

KW - molecular genetics

KW - mosaic recombination

KW - parental sex bias

KW - site-specific recombinase

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UR - https://www.scopus.com/pages/publications/85082824559#tab=citedBy

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DO - 10.1016/j.neuron.2020.01.008

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AN - SCOPUS:85082824559

SN - 0896-6273

VL - 106

SP - 37-65.e5

JO - Neuron

JF - Neuron

IS - 1

ER -

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

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