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Genotyping Protocol
The floxed allele of Kdm5c is used to knock out expression. The model recapitulates adaptive and cognitive abnormalities observed in X-linked intellectual disability in humans, including impaired social behavior, memory deficits, and aggression. Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels. Also developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Other papers will soon report that Kdm5c contributes to sex differences in disease phenotypes because Kdm5c is expressed higher in XX cells than XY cells.
Conditional phenotype:PMID:26804915 reported cognitive and neural deficits in males with the KO allele. A report has been submitted from UCLA reporting that deletion of one allele in XX females reduces body weight and adiposity, making XX (+/-) mice similar to XY mice.
Note:The donating investigator (Arthur Arnold, UCLA) received the mixed-strain mouse line with the floxed allele of Kdm5c from the Yang Shi lab, and backcrossed the line to C57BL/6J for more than 10 generations. Kdm5c is an important developmental disability gene in humans. In addition, this gene is X-linked and escapes X inactivation, so it is expressed higher in XX than XY cells. This inherent sex difference in expression causes sex differences in protection from disease, as unpublished papers will soon report. This line is part of an integrated set of mouse resources that Arnold has contributed to the MMRRC, and is an important new addition that will be highly valued by other investigators studying sex differences caused by X chromosome genes.
Iwase, Shi et al. (PMID:26804915) disrupted Kdm5c function in mice through targeted elimination of exons 11 and 12, which encode its enzymatic domain. This knockout strategy is predicted to generate a mutant Kdm5c gene encoding an RNA transcript with an in-frame deletion of exons 11 and 12. Nonetheless, the predicted mutant Kdm5c protein is barely detectable in the knockout, and the estimated level of expression is less than 5% of the wild-type Kdm5c protein level.
Iwase S, Brookes E, Agarwal S, Badeaux AI, Ito H, Vallianatos CN, Tomassy GS, Kasza T, Lin G, Thompson A, Gu L, Kwan KY, Chen C, Sartor MA, Egan B, Xu J, ShiY. A Mouse Model of X-linked Intellectual Disability Associated with ImpairedRemoval of Histone Methylation. Cell Rep. 2016 Feb 9;14(5):1000-1009. doi:10.1016/j.celrep.2015.12.091. Epub 2016 Jan 21. (Medline PMID: 26804915)
Scandaglia M, Lopez-Atalaya JP, Medrano-Fernandez A, Lopez-Cascales MT, DelBlanco B, Lipinski M, Benito E, Olivares R, Iwase S, Shi Y, Barco A. Loss ofKdm5c Causes Spurious Transcription and Prevents the Fine-Tuning ofActivity-Regulated Enhancers in Neurons. Cell Rep. 2017 Oct 3;21(1):47-59. doi:10.1016/j.celrep.2017.09.014. (Medline PMID: 28978483)
Colony Surveillance Program and Current Health Reports
Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.
Cryopreserved material may be available upon request, please inquire to mmrrc@ucdavis.edu for more information.
Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.
The donor or their institution limits the distribution to non-profit institutions only.
Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.
1 The distribution fee covers the expense of rederiving mice from a live mouse; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.
2 An aliquot contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.
3 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.
4 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.