Overview

Also Known As:16p11.2^-, 16p11^-

A copy number variation on human chromosome 16p11.2 is among the most common genetic variations found in autism spectrum disorders. The 16p11^- allele has the syntenic 440 kbp region on mouse chromosome 7F3 deleted (between and including Coro1a to Spn) and also expresses a fluorescent reporter gene (mCherry) under the control of the CAG promoter. These mice may be useful in studying basal ganglia circuitry and the pathophysiology of autism.

Donating Investigator

Jacqueline N Crawley, University of California Davis School of Medicine

Ricardo E Dolmetsch, Stanford University

Genetic overview

Genetic Background	Generation

Del(7Coro1a-Spn)1Dolm

Allele Type	Gene Symbol	Gene Name
Targeted (Reporter, Null/Knockout)	Del(7Coro1a-Spn)1Dolm	deletion, Chr 7, Ricardo Dolmetsch 1

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Research Applications

Developmental Biology Research
Neurobiology Research
Sensorineural Research
Research Tools

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

This strain description is for 16p11^- mice on a predominantly C57BL/6N genetic background. Because the live colony at The Jackson Laboratory is maintained by breeding B6129SF1/J (Stock No. 101043) with heterozygous 16p11^- males every generation, the phenotype of the 16p11^- mice distributed from The Jackson Laboratory Stock No. 025100 could vary from that shown below. We may modify the strain description if necessary as published results become available.

A copy number variation (CNV) on human chromosome 16p11.2 is among the most common genetic variations found in autism spectrum disorders (ASD). Patients with this deletion display motor deficits, speech/language delay, and cognitive impairments, accompanied by ASD, attention deficit hyperactivity disorder (ADHD), seizures, and hearing disorders. Conversely, a duplication of 16p11.2 is associated with schizophrenia. The chromosome 16p11.2 CNV encompasses 26 genes that are highly conserved on mouse chromosome 7F3.

The 16p11^- allele has the syntenic 440 kbp 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 promoter. Heterozygous mice (16p11^+/-) are viable and fertile, but are visibly smaller and leaner with impaired early postnatal survival (see additional breeding notes below). 16p11^+/- mice exhibit normal social behavior but show hyperactivity, circling and deficits in movement control, hearing (deaf), and habituation to familiarity. Heterozygotes have anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mice: abnormalities in the basal ganglia circuitry, elevated dopamine D2 receptor (Drd2+) expressing striatal medium spiny neurons and fewer dopamine-sensitive (Drd1+) neurons in deep layers of cortex. For imaging large-scale anatomical structures, such as white matter tracts, mCherry fluorescence is very strong. For identification of single neuronal cell-bodies, however, immunohistochemical fluorescence might improve the outcome.

The donating investigator reports the following breeding characteristics. Heterozygous females do not take care of their pups. Breeding 16p11^+/- animals together never resulted in homozygous pups. To improve pup survival, breeding cages may be supplemented with high-fat chow and fresh fruit (apples and oranges). Removing wildtype littermates by postnatal day 6 reduces food competition and is very effective in improving 16p11^+/- pup survivability. Further, 16p11^+/- pups benefit from concentrated liquid dietary supplement and vitamin B12 injections (if underweight). Heterozygous mice are usually still runty at standard weaning age, and benefit from delaying wean for up to a week. All weanlings may be provided with fresh fruit supplements until 4 weeks of age. Healthy adults can be maintained on standard rodent chow and water ad libitum. Underweight adults benefit from dietary supplements.

Mice with the mouse chromosome 7F3 region flanked by several loxP and frt sites (16p11^flx) are available at The Jackson Laboratory as Stock No. 025330.

Development

The 16p11^- allele has a deletion of the 440 kbp region on mouse chromosome 7F3 (between and including Coro1a to Spn); a region highly conserved with the human chromosome 16p11.2 region whose copy number variations are associated with autism spectrum disorders and schizophrenia.

Drs. Ricardo E. Dolmetsch and Thomas Portmann (while at Stanford University) created the two targeting vectors used to generate these 16p11^- mice. The first vector was designed to insert a CMV-IE enhancer/chicken beta-actin/rabbit beta-globin hybrid promoter (from pCAGGS), loxP-frt-neomycin resistance cassette-loxP-frt-loxP sequence and polyA signal at the centromeric end of the coronin actin binding protein 1A locus (Coro1a). The insertion site was 1165 bp centromeric (transcriptionally downstream) of the last Coro1a exon to avoid disrupting endogenous expression prior to Cre recombination. The second targeting vector was designed to insert a translational stop codon (for all frames), loxP-frt-puromycin resistance cassette-loxP-frt sequence, rabbit b-globin intron, coding sequence mCherry fluorescent protein (with palmitoylation signal for membrane targeting) and polyA signal at the telomeric end of the sialophorin locus (Spn). The insertion site was 3336 bp telomeric (transcriptionally upstream) of the Spn gene to avoid disrupting endogenous expression prior to Cre recombination. Sequential targeting into 129 mouse embryonic stem cells (mESC [see note below]) resulted in mESC clones with cis arrangement (targeting into the same chromosome 7 homolog) or trans arrangement (each vector targeted into different chromosome 7 homologs). The modified mESCs were injected into blastocysts, implanted into pseudopregnant female mice, and chimeric males were subsequently bred to C57BL/6NCrl females and/or HPRT-Cre females (Hprt^tm1(cre)Mnn on a C57BL/6;CD1 mixed genetic background; see Stock No. 004302). Germline transmission was successful only for the cis arrangement, and animals lacking one copy of the 16p11 genes resulted in heterozygous deletion mice (16p11^+/-). Dr. Dolmetsch bred the 16p11^+/- colony onto C57BL/6NCrl for at least three generations, and then sent 16p11^+/- mice to Dr. Jacqueline N. Crawley (while at NIMH) in 2011. Dr. Crawley took the colony to University of California Davis in 2012. Dr. Crawley maintained the colony by breeding wildtype (16p11^+/+) females with 16p11^+/- males every generation (with one mating of C57BL/6J females to 16p11^+/- males in 2013). In 2014, Dr. Crawley sent The Jackson Laboratory 16p11^+/- males on a mixed genetic background (~67% C57BL/6N, ~30% 129 [not all from 129P origin], ~3% C57BL/6J, and a region of chromosome 7 that is neither C57BL/6 nor 129 [may be CD1]).
Upon arrival, sperm from an agouti male was cryopreserved. To establish our living colony, an aliquot of frozen sperm was used to fertilize B6129SF1/J oocytes (Stock No. 101043). When maintaining a live colony at The Jackson Laboratory, B6129SF1/J (Stock No. 101043) females are bred with heterozygous males every generation.

Although the Portmann et al. 2014 Cell Rep 7(4):1077-92 publication describes the mESC used were 129/OLA, the donating laboratory indicates it may have been a different 129 origin. It is not known if the 16p11^+/- mice we received retained the mESC-derived allele(s) at the tyrosinase locus (e.g., Tyr^c and/or Tyr^c-ch) that, because it is only ~40 kbp proximal on chromosome 7, would segregate along with the 16p11^- region.

Expression Data

Expressed Gene	RFP, Red Fluorescent Protein, coral
Site of Expression	Basal ganglia in cortex and striatum of juvenile mutant mice.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Portmann T; Yang M; Mao R; Panagiotakos G; Ellegood J; Dolen G; Bader PL; Grueter BA; Goold C; Fisher E; Clifford K; Rengarajan P; Kalikhman D; Loureiro D; Saw NL; Zhengqui Z; Miller MA; Lerch JP; Henkelman RM; Shamloo M; Malenka RC; Crawley JN; Dolmetsch RE. 2014. Behavioral abnormalities and circuit defects in the Basal Ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Rep 7(4):1077-92PubMed: 24794428 MGI: J:210018

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Genetics

Del(7Coro1a-Spn)1Dolm

Allele Symbol: Del(7Coro1a-Spn)1Dolm

Allele Name	deletion, Chr 7, Ricardo Dolmetsch 1
Allele Type	Targeted (Reporter, Null/Knockout)
Allele Synonym(s)	16p11.2; 16p11^-
Gene Symbol and Name	Del(7Coro1a-Spn)1Dolm, deletion, Chr 7, Ricardo Dolmetsch 1
Gene Synonym(s)
Expressed Gene	RFP, Red Fluorescent Protein, coral
Site of Expression	Basal ganglia in cortex and striatum of juvenile mutant mice.
Strain of Origin	129P2/OlaHsd
Chromosome	7
Molecular Note	Two sequential targeting events generated Igs14^tm1Dolm and Igs13^tm1Dolm. Cre-mediated recombination removed both floxed neomycin cassettes creating a deletion that spans 440 kbp region on mouse chromosome 7F3 (between and including Coro1a to Spn); a region highly conserved with the human chromosome 16p11.2 region whose copy number variations are associated with autism spectrum disorders and schizophrenia.

Disease/Phenotype

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

autism spectrum disorder

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Developmental Biology Research
- Neurodevelopmental Defects
- Perinatal Lethality
Neurobiology Research
- Behavioral and Learning Defects
- Hearing Defects
- Fluorescent protein expression in neural tissue
- Ataxia (Movement) Defects
- Cortical Defects
- Neurodevelopmental Defects
  - Autism
Sensorineural Research
- Hearing Defects
Research Tools
- Fluorescent Proteins

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Del(7Coro1a-Spn)1Dolm/+
involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6N * CD-1

adipose tissue phenotype

abnormal abdominal fat pad morphology
- reduction in accumulation of abdominal fat pads

behavior/neurological phenotype

hyperactivity

tremors

growth/size/body region phenotype

decreased body length
- 12.2% reduction in average body length as compared to controls

decreased body weight
- reduced body weight as compared to controls
- some animals recover to normal body weight as adults

mortality/aging

premature death
- some mice die in the first postnatal weeks

nervous system phenotype

abnormal basal ganglion morphology
- relative volume is unchanged
- structural abnormalities in basal ganglia are characterized by expansion in dorsofrontal direction and reduction at ventrocaudal areas

abnormal corpus callosum morphology
- morphological abnormalities in corpus callosum

abnormal excitatory postsynaptic currents
- increase in ratio of AMPAR excitatory postsynaptic currents to NMDA receptor-mediated excitatory postsynaptic currents

abnormal globus pallidus morphology
- 2.79% increase in relative volume of globus pallidus

abnormal medium spiny neuron morphology
- increased numbers of Drd2+ striatal medium spiny neurons

abnormal miniature excitatory postsynaptic currents
- increase in mean miniature excitatory postsynaptic current frequency

abnormal nucleus accumbens morphology
- 4.83% increase in relative volume of nucleus accumbens

decreased brain weight
- mildly reduced brain weight and volume in P7 pups, however, brain weight matches controls as mice mature

decreased paired-pulse facilitation
- decrease in paired-pulse ratios across multiple interstimulus intervals

hypothalamus hyperplasia
- increase in size of hypothalamus (4.2%)

increased inferior colliculus size
- increase in size of superior and inferior colliculi (5.9% and 11.7%, respectively)

increased superior colliculus size
- increase in size of superior and inferior colliculi (5.9% and 11.7%, respectively)

thalamus hyperplasia
- increase in size of thalamus (9.6%)

thickened cerebral cortex
- increased thickness in medial areas of cortex

thin cerebral cortex
- reduced thickness in lateral and ventral areas of cortex

Genotype: Del(7Coro1a-Spn)1Dolm/+
B6N.129P2(Cg)-Del(7Coro1a-Spn)1Dolm

behavior/neurological phenotype

abnormal gait
- decrease in fluid gait observed in 19.4% of 8-12 week old mice

abnormal habituation to a novel object
- mice do not become habituated to novel objects

abnormal response to novel object
- mice do not display a preference for novel objects over familiar objects

absent startle reflex
- mice lack a startle response to sounds at 100 db, 110 db, and 120 db, however, mice respond to air puffs

circling
- increase in circling behavior observed in 8-12 week old mice in 18.75% of mice

decreased grooming behavior
- decreased self grooming observed in 8-12 week old mice in dark home cage environment

hyperactivity
- less resting observed in 8-12 week old mice in dark home cage environment
- mice cover 2.5 times more distance than controls as observed in 8-12 week old mice in dark home cage environment

hypoactivity
- hypoactivity initially observed in open-field test in novel environment, however, hypoactivity disappears in first 10 minutes

impaired coordination
- increased hanging observed in 8-12 week old mice in dark home cage environment

tremors
- tremor exhibited by 19.4% of 8-12 week old mice

hearing/vestibular/ear phenotype

impaired hearing

References

Portmann T; Yang M; Mao R; Panagiotakos G; Ellegood J; Dolen G; Bader PL; Grueter BA; Goold C; Fisher E; Clifford K; Rengarajan P; Kalikhman D; Loureiro D; Saw NL; Zhengqui Z; Miller MA; Lerch JP; Henkelman RM; Shamloo M; Malenka RC; Crawley JN; Dolmetsch RE. 2014. Behavioral abnormalities and circuit defects in the Basal Ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Rep 7(4):1077-92PubMed: 24794428 MGI: J:210018

Additional - Del(7Coro1a-Spn)1Dolm related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Del(7Coro1a-Spn)Dolm-alternate 1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, the donating investigator routinely breeds wildtype females with heterozygous males. When maintaining a live colony at The Jackson Laboratory, B6129SF1/J (Stock No. 101043) females are bred with heterozygous males every generation.

Heterozygous mice (16p11^+/-) are viable and fertile, but are visibly smaller and leaner with impaired early postnatal survival. The donating investigator reports the following breeding characteristics. Heterozygous females do not take care of their pups. Breeding 16p11^+/- animals together never resulted in homozygous pups. To improve pup survival, breeding cages may be supplemented with high-fat chow and fresh fruit (apples and oranges). Removing wildtype littermates by postnatal day 6 reduces food competition and is very effective in improving 16p11^+/- pup survivability. Further, 16p11^+/- pups benefit from concentrated liquid dietary supplement and vitamin B12 injections (if underweight). Heterozygous mice are usually still runty at standard weaning age, and benefit from delaying wean for up to a week. All weanlings may be provided with fresh fruit supplements until 4 weeks of age. Healthy adults can be maintained on standard rodent chow and water ad libitum. Underweight adults benefit from dietary supplements.

Although the Portmann et al. 2014 Cell Rep 7(4):1077-92 publication describes the mESC used were 129/OLA, the donating laboratory indicates it may have been a different 129 origin. It is not known if the 16p11^+/- mice we received retained the mESC-derived allele(s) at the tyrosinase locus (e.g., Tyr^c and/or Tyr^c-ch) that, because it is only ~40 kbp proximal on chromosome 7, would segregate along with the 16p11^- region.
- Additional Breeding and Husbandry Support
Citation
When using the 16p11.2^- mouse strain in a publication, please cite the originating article(s) and include JAX stock #025100 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

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Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or Wildtype for Del(7Coro1a-Spn)1Dolm

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Also Known As:16p11.2-, 16p11-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Del(7Coro1a-Spn)1Dolm

Allele Symbol: Del(7Coro1a-Spn)1Dolm

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Del(7Coro1a-Spn)1Dolm/+involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6N * CD-1

adipose tissue phenotype

behavior/neurological phenotype

growth/size/body region phenotype

mortality/aging

nervous system phenotype

Genotype: Del(7Coro1a-Spn)1Dolm/+B6N.129P2(Cg)-Del(7Coro1a-Spn)1Dolm

behavior/neurological phenotype

hearing/vestibular/ear phenotype

References

Additional - Del(7Coro1a-Spn)1Dolm related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:16p11.2^-, 16p11^-

Genotype: Del(7Coro1a-Spn)1Dolm/+
involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6N * CD-1

Genotype: Del(7Coro1a-Spn)1Dolm/+
B6N.129P2(Cg)-Del(7Coro1a-Spn)1Dolm