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Autism mouse models

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SFARI and The Jackson Laboratory are collaborating to increase the availability of autism mouse models to the research community.

Mouse models are essential to advance understanding of the mechanistic basis of autism spectrum disorders, as well as to test potential therapies. There is a growing list of models with good construct validity — meaning that they carry a mutation in a known risk gene — and face validity, or bearing some physical or behavioral resemblance to the human disorder.

Still, there remain significant barriers to the rapid distribution of these resources from individual academic labs. SFARI has made a commitment to establish colonies of the best of these models at The Jackson Laboratory, which will allow any interested researcher to gain access to them in the shortest amount of time possible and at minimal cost.

Click here for more information on the rationale for this initiative and other related mouse projects.

The following mouse lines are either currently or soon to be available from The Jackson Laboratory. We are grateful to the principal investigators whose labs generated these mice for making these valuable resources available to the community.

Researchers who are interested in ordering these mice and would like more information should contact Cathleen Lutz at The Jackson Laboratory ([email protected]).

Researchers who are interested in having a particular mutant mouse placed at The Jackson Laboratory should send a brief description of the mouse and a rationale for its inclusion to [email protected].

Available (or soon to be available) mouse models

16p11.2 deletion

Donating investigator/institution: Alea Mills, Ph.D./Cold Spring Harbor Laboratory

Description: These mutant mice possess an engineered deletion spanning approximately 0.39 megabases on mouse chromosome 7, a region that shares conserved synteny with human chromosome 161.

16p11.2 deletion

Donating investigators/institutions: Ricardo Dolmetsch, Ph.D./Stanford University; Jacqueline Crawley, Ph.D./University of California Davis School of Medicine

Description: This line has the syntenic 440 kilobase-pair region on mouse chromosome 7F3 deleted (between and including CORO1A to SPN) and also expresses a membrane-targeted fluorescent reporter gene (mCherry) under the control of the CAG promoter2.

16p11.2 duplication

Donating investigator/institution: Alea Mills, Ph.D./Cold Spring Harbor Laboratory

Description: These mutant mice possess an engineered duplication of approximately 0.39 megabases of mouse chromosome 7, a region that shares conserved synteny with human chromosome 161.

CACNA1C (TS2-neo) mutation

Donating investigator/institution: Randall Rasmusson, Ph.D./University of Buffalo, The State University of New York

Description: These mutant mice harbor a G406R mutation in exon 8a, as well as an inverted neo cassette3.

CNTNAP2 (CASPR2) deletion

Donating investigator/institution: Elior Peles, Ph.D./Weizmann Institute of Science

Description: CNTNAP2-null mice were generated by a standard gene-targeting approach, resulting in the replacement of its first exon, which includes the translation initiation site and its signal sequence with a neo gene4,5.

CUL3 floxed

Donating investigator/institution: Jeffrey Singer, Ph.D./Portland State University

Description: CUL3flox (loxP::frt-neo-frt::exons4-7::loxP) is a cullin 3 hypomorphic allele that is converted to a null allele after Cre recombinase exposure6.

DYRK1A floxed

Donating investigator/institution: John D. Crispino, Ph.D./Northwestern University

Description: These floxed mutant mice possess loxP sites flanking exons 5 and 6 of the DYRK1A gene7.

GTF2I duplication

Donating investigator/institution: Lucy Osborne, Ph.D./University of Toronto; Jacqueline Crawley, Ph.D./University of California, Davis

Description: The GTF2I duplication allele has one additional copy of a functional mouse general transcription factor 2I (TFII-I). This gene is within the region implicated in 7q11.23 duplication syndrome8.

SHANK3 deletion

Donating investigator/institution: Joseph Buxbaum, Ph.D./Mount Sinai School of Medicine

Description: These mutant mice harbor a deletion of the SH3/ankyrin domain gene 3 (SHANK3) ankyrin repeat domains (exons 4-9); this deletion prevents full-length SHANK3 expression9.

SHANK3 deletion

Donating investigator/institution: Guoping Feng, Ph.D./Duke University

Description: These mutant mice harbor a deletion of the PDZ domain, which eliminates expression of the ‘A’ and ‘B’ isoforms10.

SYNGAP1 conditional deletion

Donating investigator/institution: Gavin Rumbaugh, Ph.D./The Scripps Research Institute

Description: These mice have an insertion of a loxP sequences flanking exons 6 to 7 of the SYNGAP1 gene. Upon Cre-mediated deletion, this strategy results in the deletion of the sequences encoding for the PH domain and possibly part of the C2 domain, resulting in an out-of-frame deletion and ablation of the targeted allele11.

  • In transit to The Jackson Laboratory

SYNGAP1 conditional rescue

Donating investigator/institution: Gavin Rumbaugh, Ph.D./The Scripps Research Institute

Description: These mice have an insertion of a loxP_Neo-STOP_loxP cassette within intron 5 of the SYNGAP1 gene. This leads to a premature arrest of SYNGAP translation and ablation of the targeted allele. Upon Cre-mediated deletion of the inserted cassette, endogenous SYNGAP expression is restored11.

  • In transit to The Jackson Laboratory

UBE3A variant 1 overexpression

Donating investigator/institution: Scott Dindot, Ph.D./Texas A&M University

Description: These transgenic mice allow Tet-off/ Tet-on expression of a FLAG-tagged UBE3A splice variant 1 protein, in addition to normal expression of endogenous UBE3A. Funded in collaboration with Dup15q Alliance.

UBE3A variant 2 overexpression

Donating investigator/institution: Scott Dindot, Ph.D./Texas A&M University

Description: These transgenic mice allow Tet-off/ Tet-on expression of a FLAG-tagged UBE3A splice variant 2 protein, in addition to normal expression of endogenous UBE3A. Funded in collaboration with Dup15q Alliance.

UBE3A variant 2, 3 overexpression

Donating investigator/institution: Matthew Anderson, M.D., Ph.D./Beth Israel Deaconess Medical Center, Harvard Medical School

Description: These transgenic mice allow expression of FLAG-tagged UBE3A long isoforms (splice variants 2 and 3, L), in addition to endogenous UBE3A12.

We are in the process of identifying additional lines of mutant mice that hold sufficient promise as models of autism spectrum disorders. We will update this page as soon as new models become available.

Mouse behavioral phenotyping

SFARI is collaborating with Roche Pharmaceuticals and PsychoGenics Inc. to further characterize several of the mouse models listed above. The experimental approach includes assays of core autism domains using standardized tests as well as novel, computer-vision based systems. The first paper describing results from the 16p11.2 deletion1 and CNTNAP2 deletion4,5 models has recently been published13. A second paper describing results from the CACNA1C(TS2-neo)3 and two SHANK3 deletion10,14 models is forthcoming (a preprint is available at bioRxiv15).

In addition, raw behavioral phenotyping data on the 16p11.2 deletion1, CNTNAP24,5 and SHANK310 mouse models (generated by SFARI grants to Ted Abel and Sandeep Robert Datta) will be available in the coming months via SFARI Base. Abel’s project consisted of a comprehensive behavioral battery, including over a dozen paradigms and testing of both sexes at multiple developmental timepoints. Datta’s project incorporated his novel 3D computer vision/unsupervised machine-learning approach, the methodology of which was recently published16.

References:

  1. Horev G. et al. Proc. Natl. Acad. Sci. USA 108, 17076-17081 (2011) PubMed
  2. Portmann T. et al. Cell Rep. 7, 1077-1092 (2014) PubMed
  3. Bader P.L. et al. Proc. Natl. Acad. Sci. USA 108, 15432-15437 (2011) PubMed
  4. Poliak S. et al. J. Cell Biol. 162, 1149-1160 (2003) PubMed
  5. Peñagarikano O. et al. Cell 147, 235-246 (2011) PubMed
  6. McEvoy J.D. et al. Mol. Cell. Biol. 27, 3651-3656 (2007) PubMed
  7. Thompson B.J. et al. J. Exp. Med. 212, 953-970 (2015) PubMed
  8. Mervis C.B. et al. Am. J. Hum. Genet. 90, 1064-1070 (2012) PubMed
  9. Bozdagi O. et al. Mol. Autism 1, 15 (2010) PubMed
  10. Peça J. et al. Nature 472, 437-442 (2011) PubMed
  11. Clement J.P. et al. Cell 151, 709-723 (2012) PubMed
  12. Smith S.E. et al. Sci. Transl. Med. 3, 103ra197 (2011) PubMed
  13. Brunner D. et al. PLoS One 10, e0134572 (2015) PubMed
  14. Wang X. et al. Hum. Mol. Genet. 20, 3093-3108 (2011) PubMed
  15. Kabitzke P.A. et al. bioRxiv (2016) Preprint
  16. Wiltschko A.B. et al. Neuron 88, 1112-1135 (2015) PubMed