Phenotypes associated with this allele

• Allele Symbol: Cdk5r1^tm1Lht
• Allele Name: targeted mutation 1, Li-Huei Tsai
• Allele ID: MGI:1931885
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cdk5r1^tm1Lht/Cdk5r1^tm1Lht	involves: 129S4/SvJae	MGI:3721424
hm2	Cdk5r1^tm1Lht/Cdk5r1^tm1Lht	involves: 129S4/SvJae * C57BL/6	MGI:2175756
cx3	Cdk5r1^tm1Lht/Cdk5r1^tm1Lht Cdk5r2^tm1Lht/Cdk5r2^+	involves: 129S4/SvJae * C57BL/6	MGI:3721441
cx4	Cdk5r1^tm1Lht/Cdk5r1^+ Cdk5r2^tm1Lht/Cdk5r2^tm1Lht	involves: 129S4/SvJae * C57BL/6	MGI:3721440
cx5	Cdk5r1^tm1Lht/Cdk5r1^tm1Lht Cdk5r2^tm1Lht/Cdk5r2^tm1Lht	involves: 129S4/SvJae * C57BL/6	MGI:2662490

Genotype
MGI:3721424

hm1

• Allelic Composition: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht
• Genetic Background: involves: 129S4/SvJae

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:38857 )

nervous system

seizures ( J:38857 )

abnormal axon extension ( J:193542 )

• neurons fail to respond to BDNF treatment with increased spine density unlike wild-type cells

abnormal forebrain morphology ( J:38857 )

• mice on 129 inbred background show the phenotypes observed on the mixed 129Sv/C57BL/6 background

abnormal forebrain development ( J:38857 )

abnormal olfactory bulb development ( J:38857 )

dilated lateral ventricle ( J:38857 )

decreased corpus callosum size ( J:38857 , J:204269 )

• size of the corpus callosum is severely reduced (J:204269)

abnormal striatum morphology ( J:38857 )

abnormal hippocampus morphology ( J:38857 )

abnormal dentate gyrus morphology ( J:38857 )

abnormal hippocampus layer morphology ( J:38857 )

abnormal cerebral cortex morphology ( J:38857 )

abnormal stratification in cerebral cortex ( J:204269 )

• lamination of the cerebral cortex is abnormal

ectopic Purkinje cell ( J:38857 )

abnormal cerebellar molecular layer ( J:38857 )

abnormal innervation ( J:204269 )

• tracer analysis indicates that mutants exhibit a loss in the layer-specific afferentiation of descending medial prefrontal cortex outputs projecting to the nucleus accumbens

• mice show an increased density of dopaminergic fiber innervation in the infralimbic, prelimbic, and cingulate cortices

reduced long-term potentiation ( J:193542 )

• following application of BDNF

behavior/neurological

abnormal behavioral response to xenobiotic ( J:204269 )

• mice dosed repeatedly with psychostimulants exhibit hypolocomotion, such that by the 5th day of methylphenidate (MPH) dosing, locomotor activity is reduced to 63% of controls

• mice exhibit a hypolocomotive response to repeated injections of cocaine

abnormal sensitization to xenobiotic ( J:204269 )

• mice do not exhibit sensitized responses to MPH dosing over 5 days as seen in wild-type mice

• mice are deficient in sensitization to repeated injections of cocaine

hyperactivity ( J:204269 )

• mice show hyperactivity over a 60-minute testing period compared with controls

seizures ( J:38857 )

cellular

abnormal axon extension ( J:193542 )

• neurons fail to respond to BDNF treatment with increased spine density unlike wild-type cells

increased cellular glucose import ( J:204269 )

• mice show a greater rate of glucose uptake in the cerebral cortex

homeostasis/metabolism

increased serotonin level ( J:204269 )

• mice exhibit small, but significant, elevations in basal serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels

abnormal physiological response to xenobiotic ( J:204269 )

• dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), levels are reduced in the striatum and prefrontal cortex of mice dosed with MPH for 5 days, however basal levels of both are normal

• dopamine turnover is increased in response to repeated MPH treatment compared to un-treated mutants while treatment of wild-type mice with MPH has no effect on dopamine turnover

• after chronic MPH treatment, mice show about a 51% reduction in dopamine turnover compared to chronically treated wild-type mice

• chronic MPH induces a 1.08-fold increase in 5-HT, an 18% decrease in 5-HIAA, and a 23% decrease in 5-HT turnover in mutants compared to wild-type mice

• no differences are seen in the caudate putamen after MPH treatment

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
attention deficit hyperactivity disorder		DOID:1094	OMIM:143465 OMIM:608903 OMIM:608904 OMIM:608905 OMIM:608906 OMIM:612311 OMIM:612312	J:204269

Genotype
MGI:2175756

hm2

• Allelic Composition: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

premature death ( J:38857 )

• ~15% of homozygotes die by ~4 months, starting at about 3 weeks of age

nervous system

seizures ( J:38857 )

• over long-term observation, seizures are observed

increased susceptibility to pharmacologically induced seizures ( J:38857 )

• administration of 50 mg/kg pentylenetetrazol, induces generalized convulsions (with loss of posture, myclonic jerks, hyperextension of neck and trunk associated with cycling motions of limbs and extension of hind limbs) in wild-type and mutant mice with similar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die

abnormal forebrain morphology ( J:38857 )

• in three-month old mice, general disorganization of forebrain is apparent

thin cortical plate ( J:38857 )

• cortical plate is 30-50% thinner than in wild-type embryos at E15

abnormal subplate morphology ( J:71181 )

• at E18.5, an ectopic cortical subplate is detected under the most superficial cortical plate with later-born cortical neurons accumulated underneath

abnormal olfactory bulb development ( J:38857 )

• internal plexiform layer between mitral cell layer and internal granule layers is absent

dilated lateral ventricle ( J:38857 )

• lateral ventricles are ~twice the size of lateral ventricles in wild-type brain in 3-month old animals

decreased corpus callosum size ( J:38857 )

• size (thickness) is significantly reduced

decreased striatum size ( J:38857 )

• size is reduced

abnormal hippocampus morphology ( J:38857 , J:71181 )

• at E18.5, hippocampus shows signs of disorganization, but this is less severe than in double null mutants (J:71181)

abnormal dentate gyrus morphology ( J:38857 )

abnormal hippocampus layer morphology ( J:38857 )

• layers II and III are occupied by large instead of small pyramidal neurons

• most cells in hippocampus and dentate gyrus are included in a laminar structure like in wild-type, but cells are less densely packed

abnormal cerebral cortex morphology ( J:38857 , J:71181 )

• laminated structure is not apparent in 3-month old mice; defects in lamination are less severe in lateral-ventral region of cortex (J:38857)

• no recognizable pattern is observed for distribution of pyramidal, granule, and polymorphic cells in cortex (J:38857)

• mutant cortex contains aberrant fascicles in the neocortex and no fascicles are seen in the lateral-ventral portion of the cortex (J:38857)

• radial distribution of pyramidal neurons and their apical dendrites is not conspicuous like in wild-type brains (J:38857)

• cortex shows mild neuronal-positioning abnormalities (J:71181)

abnormal cerebral cortex pyramidal cell morphology ( J:38857 )

• orientation of neuronal soma and direction of dendritic growth are altered; defect is more severe in medial neocortex

ectopic Purkinje cell ( J:38857 )

• some cells are located in granule cell layer

abnormal cerebellar molecular layer ( J:38857 )

• molecular layer shows a greater cell density than wild-type, and contains cells resembling granule cells

behavior/neurological

seizures ( J:38857 )

• over long-term observation, seizures are observed

increased susceptibility to pharmacologically induced seizures ( J:38857 )

• administration of 50 mg/kg pentylenetetrazol, induces generalized convulsions (with loss of posture, myclonic jerks, hyperextension of neck and trunk associated with cycling motions of limbs and extension of hind limbs) in wild-type and mutant mice with similar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die

Genotype
MGI:3721441

cx3

• Allelic Composition: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht; Cdk5r2^tm1Lht/Cdk5r2⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

premature death ( J:71181 )

• viability decreases with age, with mortality observed starting by P60

nervous system

nervous system phenotype ( J:71181 )

N • hippocampus is comparable to wild-type

abnormal hippocampus layer morphology ( J:71181 )

• diffuse laminar organization of CA pyramidal neurons; cell-free rifts appear less conspicuous than in double null animals

abnormal cerebellum morphology ( J:71181 )

• fissura secuda is less prominent than in wild-type or single-mutant cerebella at E18.5

small cerebellum ( J:71181 )

• decreased size relative to wild-type or single-null mice at E18.5

Genotype
MGI:3721440

cx4

• Allelic Composition: Cdk5r1^tm1Lht/Cdk5r1⁺; Cdk5r2^tm1Lht/Cdk5r2^tm1Lht
• Genetic Background: involves: 129S4/SvJae * C57BL/6

nervous system

abnormal neuron differentiation ( J:71181 )

• obliquely oriented clumps of neurons are more prominent in cerebral walls than in Cdk5r1-null mice

abnormal cortical marginal zone morphology ( J:71181 )

• marginal zone is obscured

thin cortical plate ( J:71181 )

abnormal hippocampus layer morphology ( J:71181 )

• lamination defects are observed

abnormal cerebellum morphology ( J:71181 )

• fissura secuda is less prominent than in wild-type or single-mutant cerebella at E18.5

small cerebellum ( J:71181 )

• decreased size relative to wild-type or single-null mice at E18.5

cellular

abnormal neuron differentiation ( J:71181 )

• obliquely oriented clumps of neurons are more prominent in cerebral walls than in Cdk5r1-null mice

Genotype
MGI:2662490

cx5

• Allelic Composition: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht; Cdk5r2^tm1Lht/Cdk5r2^tm1Lht
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

perinatal lethality, incomplete penetrance ( J:71181 )

• frequency of homozygous pups at birth is 2.8%, compared to expected 6.25%; mice do not survive past P0

• number of double homozygotes found at E18.5 is increased over numbers at birth

embryo

decreased embryo size ( J:71181 )

• at E18.5 mutant embryos are smaller than controls and at P0, pups appear runted

growth/size/body

decreased embryo size ( J:71181 )

• at E18.5 mutant embryos are smaller than controls and at P0, pups appear runted

nervous system

abnormal neuron differentiation ( J:71181 )

• axon tracts course through cortex aberrantly, oblique to the pial surface

abnormal cortical marginal zone morphology ( J:71181 )

• definition of marginal zone and cortical subplate has distorted definition

abnormal cortical plate morphology ( J:71181 )

• cortical plate is misplaced beneath superficial subplate structure

thin cortical plate ( J:71181 )

abnormal cerebellum development ( J:71181 )

absent cerebellar foliation ( J:71181 )

• complete lack of foliation at E18.5

abnormal cerebellum external granule cell layer morphology ( J:71181 )

• layer is thicker near germinal zone of rhombic lip

abnormal olfactory bulb development ( J:71181 )

• compact layer of mitral cells is absent at E18.5

• various fiber tracts show disrupted formation; medial lemniscus is intact, but other tracts aren't visible such as the solitary tract

• superior and inferior olivary nuclei are absent

abnormal dentate gyrus morphology ( J:71181 )

• indiscernible throughout entire hippocampal formation

abnormal hippocampus layer morphology ( J:71181 )

• diffuse laminar organization of CA pyramidal neurons with appearance of cell-free rifts between clusters of cells

abnormal cerebral cortex morphology ( J:71181 )

• cortex shows lamination defects and neuronal-positioning abnormalities

absent Purkinje cell layer ( J:71181 )

• this layer is absent; Purkinje cells are clustered near posterior lobe of cerebellum at E18.5

small cerebellum ( J:71181 )

• cerebellum is smaller in size relative to wild-type littermates

abnormal motor neuron morphology ( J:71181 )

• motor neurons in spinal cord display pathological changes, including chromatolysis at E18.5

chromatolysis ( J:71181 )

• seen in some motor neurons at E18.5

behavior/neurological

unresponsive to tactile stimuli ( J:71181 )

• no response to clamp stimulation of tails at P0

weakness ( J:71181 )

• at P0, surviving double homozygotes show weakness of movement

cellular

abnormal neuron differentiation ( J:71181 )

• axon tracts course through cortex aberrantly, oblique to the pial surface