B6.129(FVB)-Cdkl5^tm1.1Joez/J

Stock number: 021967
Product name: Cdkl5 KO
Research areas: Developmental Biology Research, Neurobiology Research

Description

Cdkl5 knockout mice exhibit autistic-like behavioral abnormalities, deficits in neural circuit communication, and alterations in multiple signal transduction pathways. They may be useful when studying neurodevelopmental disorders such as Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy.

Detailed description

Cyclin-dependent kinase-like 5 (Cdkl5) is an X-linked gene encoding a serine/threonine kinase that is highly expressed in the brain. Genetic mutations that disrupt CDKL5 function have been found in humans with neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy 2 (EIEE2). These individuals, classified under CDKL5 Disorder for the common genetic defect, are characterized by early-onset seizures, intellectual disability, and autistic features.

Cdkl5 knockout mice, lacking exon 6 of Cdkl5 (corresponding to exon 7 of human CDKL5), were developed to mimic a splice mutation found in humans that results in the skipping of exon 7, generating a premature stop codon and really truncation CDKL5 in its N-terminal kinase domain. Male carriers show autistic-like behavioral abnormalities, hyperactivity, motor impairments, decreased anxiety, deficits in social interaction, and impaired learning and memory with absence of spontaneous seizures. They also exhibit deficits in neural circuit communication. Cdkl5 knockout males have alterations in phosphorylation profiles in forebrain regions including the striatum, somatosensory cortex, and hippocampus where CDKL5 is expressed. Multiple signal transduction pathways, including AKT-mTOR cascade, are disrupted in Cdkl5 knockout mice. Mice that are homozygous for this allele are viable and fertile.

Of note, the floxed version of this allele is available as Stock No. 030523.

Development

A targeting vector was designed to insert a loxP-flanked neomycin resistance (neo) cassette upstream of exon 6, and a single loxP site downstream of exon 6 of the X-linked cyclin-dependent kinase-like 5 (Cdkl5) gene. The construct was electroporated into 129 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and resulting chimeric mice were bred with B6.FVB-Tg(EIIa-cre)C5379Lmgd/J mice (Stock No. 003724) to remove the neo cassette and exon 6. Resulting offspring were bred to C57BL/6J mice for at least 10 generations to establish a colony of Cdkl5 knockout mice. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation.

Allele

Symbol: Cdkl5^tm1.1Joez
Name: targeted mutation 1.1, Zhaolan Zhou
MGI accession ID: MGI:5475468
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Cdkl5
Marker name: cyclin-dependent kinase-like 5
Marker synonyms: CFAP247; DEE2; EIEE2; ISSX; Stk9
Chromosome: X
Strain of origin: 129
Molecular note: A floxed neo cassette was inserted upstream of exon 6. A loxP site was inserted downstream of exon 6. Cre-mediated recombination removed the neo cassette and exon 6. Western blot analysis confirmed the absence of protein expression.