Phenotypes associated with this allele

• Allele Symbol: Htt^tm1Mem
• Allele Name: targeted mutation 1, Marcy E MacDonald
• Allele ID: MGI:1857180
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Htt^tm1Mem/Htt^tm1Mem	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CD-1	MGI:2176494
ht2	Htt^tm1Mem/Htt^+	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CD-1	MGI:3766394
ht3	Htt^tm1Mem/Htt^tm6Mem	involves: 129S1/Sv * 129X1/SvJ * Swiss Webster	MGI:3698411
ht4	Htt^tm1Mem/Htt^tm7Mem	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * CD-1	MGI:3698007
ht5	Htt^tm1Mem/Htt^tm3Mem	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * CD-1	MGI:3698009
cn6	Htt^tm1Mem/Htt^tm6Mem Tg(CAG-cre/Esr1*)5Amc/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA * Swiss Webster	MGI:7266814

Genotype
MGI:2176494

hm1

• Allelic Composition: Htt^tm1Mem/Htt^tm1Mem
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CD-1

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

mortality/aging

embryonic lethality between somite formation and embryo turning, complete penetrance ( J:27183 )

• by E8.5, all homozygous embryos are being resorbed, while only resorption sites are found at E9.5

embryo

abnormal developmental patterning ( J:27183 )

abnormal ectoderm development ( J:27183 )

• embryonic ectoderm is symmetrical and featureless, without evidence of head folds

• ectoderm is thicker than normal, and is disorganized rather than columnar especially distally

increased ectoderm apoptosis ( J:27183 )

• ~10% of cells are pyknotic compared to <1% in normal embryos

decreased embryo size ( J:27183 )

• at E7.5, homozygous embryos are ~2/3 of normal size and misshapen; at E7.0, some homozygous embryos are observed to be smaller and thinner than other embryos in the litter

abnormal embryonic tissue morphology ( J:27183 )

• embryonic region appears shrunken at E7.5

absent primitive node ( J:27183 )

• at E7.5, primitive streak at one end of embryos forms, but no node structure is evident

embryonic-extraembryonic boundary constriction ( J:27183 )

• at E7.5, there is prominent constriction between the extraembryonic and embryonic regions of homozygotes

abnormal extraembryonic tissue morphology ( J:27183 )

• at E7.5, extraembryonic region is reduced in size

abnormal extraembryonic endoderm formation ( J:27183 )

• columnar cells of endoderm are not organized into tight sheath as in normal embryos, but form a folded layer extending around shrunken embryonic region

abnormal extraembryonic mesoderm development ( J:27183 )

• mesoderm cells line yolk sac, amnion, and chorion, but do not extend to distal pole

• cells are abnormally rounded and densely, not loosely, packed

growth/size/body

decreased embryo size ( J:27183 )

• at E7.5, homozygous embryos are ~2/3 of normal size and misshapen; at E7.0, some homozygous embryos are observed to be smaller and thinner than other embryos in the litter

cellular

increased ectoderm apoptosis ( J:27183 )

• ~10% of cells are pyknotic compared to <1% in normal embryos

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
NOT	Huntington's disease	DOID:12858	OMIM:143100	J:27183

Genotype
MGI:3766394

ht2

• Allelic Composition: Htt^tm1Mem/Htt⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CD-1

normal phenotype

no abnormal phenotype detected ( J:27183 )

• animals are normal is size and appearance, with no obvious behavioral or morphological abnormalities

Genotype
MGI:3698411

ht3

• Allelic Composition: Htt^tm1Mem/Htt^tm6Mem
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * Swiss Webster

behavior/neurological

abnormal motor capabilities/coordination/movement ( J:72915 )

• exhibit movement abnormalities that are variable from week to week but do not worsen over time

• however, mutants do not develop paralysis or the progressive movement disorder seen in Hdh^tm6Mem and Hdh^tm8Mem compound heterozygotes

growth/size/body

decreased body size ( J:72915 )

• smaller throughout life

nervous system

enlarged lateral ventricles ( J:72915 )

• 3 of 7 adults have enlarged vesicles

Genotype
MGI:3698007

ht4

• Allelic Composition: Htt^tm1Mem/Htt^tm7Mem
• Genetic Background: involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * CD-1

mortality/aging

perinatal lethality, complete penetrance ( J:44391 )

• no mutants observed at weaning but some are present as stillborn pups

lethality throughout fetal growth and development, incomplete penetrance ( J:44391 )

• the expected numbers are seen at E18.5, however 7 of 18 are either dead or in the process of being absorbed, indicating that some die before E18.5

nervous system

abnormal cerebellum development ( J:44391 )

• cerebellum is misshapen and appears underdeveloped

abnormal brain ventricle morphology ( J:44391 )

• the tightly organized layer of neuroepithelium at the ventricular surface is absent or is replaced or obscured by Map2 immunoreactive postmitotic neuronal cells

abnormal midbrain morphology ( J:44391 )

• midbrain is distorted by the abnormally large aqueduct

abnormal cerebral aqueduct morphology ( J:44391 )

• aqueduct is abnormally dilated

abnormal forebrain morphology ( J:44391 )

• forebrain is misshapen

abnormal thalamus morphology ( J:44391 )

• thalamus is malformed and displaced

abnormal telencephalon morphology ( J:44391 )

• along the midline, the entire septal area is misshapen and reduced

dilated lateral ventricle ( J:44391 )

• lateral ventricles are abnormally dilated

abnormal striatum morphology ( J:44391 )

• exhibit abnormal organization and thickening of the striatal subventricular zone

• however, the striatum does not show evidence of Huntington's disease-like pathology

abnormal hippocampus morphology ( J:44391 )

• hippocampus is malformed and displaced

absent hippocampal fimbria ( J:44391 )

• agenesis of the fimbria

abnormal olfactory bulb morphology ( J:44391 )

• olfactory bulbs are malformed and displaced

abnormal embryonic/fetal subventricular zone morphology ( J:44391 )

• display abnormal organization and thickening of the striatal subventricular zone that contains ectopic cell masses that protrude into the lateral ventricles

exencephaly ( J:44391 )

• 4 of 11 fetuses exhibit exencephaly, with the forebrain and midbrain protruding from the open skull

abnormal nervous system tract morphology ( J:44391 )

• fiber tracts exhibit extensive agenesis

cardiovascular system

abnormal blood vessel morphology ( J:44391 )

• head region is conspicuously vascularized

craniofacial

domed cranium ( J:44391 )

• domed cranium

abnormal ear position ( J:44391 )

• uni- or bilateral misplaced external ears

abnormal ear shape ( J:44391 )

• uni- or bilateral misshapen external ears

hearing/vestibular/ear

abnormal ear position ( J:44391 )

• uni- or bilateral misplaced external ears

abnormal ear shape ( J:44391 )

• uni- or bilateral misshapen external ears

skeleton

domed cranium ( J:44391 )

• domed cranium

integument

thick skin ( J:44391 )

• thickened waxy skin

growth/size/body

abnormal head morphology ( J:44391 )

• pups alive at E18.5, display a more severe head phenotype than seen in Hdh^tm7Mem homozygotes

abnormal ear position ( J:44391 )

• uni- or bilateral misplaced external ears

abnormal ear shape ( J:44391 )

• uni- or bilateral misshapen external ears

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
NOT	Huntington's disease	DOID:12858	OMIM:143100	J:44391

Genotype
MGI:3698009

ht5

• Allelic Composition: Htt^tm1Mem/Htt^tm3Mem
• Genetic Background: involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * CD-1

normal phenotype

no abnormal phenotype detected ( J:44391 )

• appear normal; none display abnormal behaviors at 6 months of age

Genotype
MGI:7266814

cn6

• Allelic Composition: Htt^tm1Mem/Htt^tm6Mem; Tg(CAG-cre/Esr1*)5Amc/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA * Swiss Webster

behavior/neurological

behavior/neurological phenotype ( J:260244 )

N • mice administered tamoxifen after P21 exhibit progressive neurological abnormalities; all abnormalities reported below are in mice treated with tamoxifen from P21-P26

limb grasping ( J:260244 )

• tamoxifen-treated mice exhibit clasping

impaired coordination ( J:260244 )

• mice administered tamoxifen from P21 to P26 exhibit abnormalities of motor coordination at 6 months of age

straub tail ( J:260244 )

• mice administered tamoxifen after P21 show Straub tail at one year of age

abnormal gait ( J:260244 )

• tamoxifen-treated mice exhibit gait disturbances at one year of age, including flattened pelvic elevation, abnormally wide hindlimb stance, and occasional hopping and stiffness

• gait abnormalities worsen over time such that 1-year-old mice lack the typical uniformity of step alternation and exhibit smaller gait strides

short stride length ( J:260244 )

• 1-year-old tamoxifen-treated mice exhibit smaller gait strides

hyperactivity ( J:260244 )

• mice administered tamoxifen from P21 to P26 exhibit a hyperkinetic phenotype at 6 months of age

environmentally induced seizures ( J:260244 )

• tamoxifen-treated mice exhibit handling induced seizures, characterized by alternating clonic movement of forelimbs, clonic and versive movements of the head, chewing movement and facial myoclonus, flagpole tail dodrsiflexion, followed by intermittent eye blinking, immobility, head nodding and clonic mouth jerks

growth/size/body

decreased body weight ( J:260244 )

• mice administered tamoxifen from P21 to P26 consistently show lower weight during adult life

muscle

muscular atrophy ( J:260244 )

• 16-month-old mice exhibit atrophy of hindlimb muscles when tamoxifen is administered after P21

nervous system

environmentally induced seizures ( J:260244 )

• tamoxifen-treated mice exhibit handling induced seizures, characterized by alternating clonic movement of forelimbs, clonic and versive movements of the head, chewing movement and facial myoclonus, flagpole tail dodrsiflexion, followed by intermittent eye blinking, immobility, head nodding and clonic mouth jerks

abnormal cerebral cortex morphology ( J:260244 )

• the number of degenerating neurons in the outer cortical layers of tamoxifen-treated mice, especially in layer III/IV is increased

abnormal primary motor cortex morphology ( J:260244 )

• layer VI thickness and numbers of neurons are reduced in the motor cortex of 12-month-old tamoxifen-treated mice

• the number of degenerating neurons in the deep layer motor cortex are increased in 12-month-old tamoxifen-treated mice

• the reduction in motor cortex layer VI is seen as early as 3 months of age, however the number of neurons in layer VI is comparable to wild-type at this age

abnormal cerebellum lobule morphology ( J:260244 )

• majority of tamoxifen-treated mice exhibit smaller cerebellar lobules

abnormal oligodendrocyte morphology ( J:260244 )

• P21 mice show fewer APC+ smooth- and ramified-type oligodendrocytes

• 3-month-old mice show a reduction of smooth- and ramified-type oligodendrocytes in layer VI of the motor cortex, with an increase of stellar-type oligodendrocytes

• however, overall number of APC+ oligodendrocytes is normal in 3-month-old tamoxifen-treated mice

• oligodendrocyte progenitors derived from primary embryonic neuronal stem cells display progressive maturation abnormalities, with impairments in the transition from proliferating progenitors to post-mitotic precursors and subsequent maturation and myelination

gliosis ( J:260244 )

• 83.3% of 12-month-old tamoxifen-treated mice exhibit striatal reactive gliosis, with exceedingly severe gliosis in the globus pallidum

astrocytosis ( J:260244 )

• reactive astrogliosis in superficial and cortical layers already at 3 months of age

abnormal nervous system development ( J:260244 )

• marker analysis indicates the presence of deficits in early neural lineage specification, migration, and regional organization, with impairments in the maturation of striatal compartmentalization

abnormal lateral ganglionic eminence morphology ( J:260244 )

• loss of the typical palisade appearance of pseudostratified neuroepithelium encompassing Mash1+ neuronal progenitors within the E15.5 lateral ganglionic eminence

ectopic neuron ( J:260244 )

• all fetuses (E14.5, E15.5, and E17.5) and early postnatal mice (P2, P10, and P21) exhibit analogous masses consisting of heterotopic evaginations of germinative zone-derived cells from the posterior ventromedial aspect of the lateral ganglionic eminence indicating subpallial ventricular heterotopias

neuronal cytoplasmic inclusions ( J:260244 )

• a number of non-degenerative cortical neurons of tamoxifen-treated mice, particularly those in layer III/IV, exhibit intracytoplasmic inclusions corresponding to concentric membrane-bound laminated inclusions of zebra bodies

neurodegeneration ( J:260244 )

• tamoxifen-treated mice develop progressive striatal neurodegenerative pathology and cortical deep layer degeneration

• 27.3% of 12-month-old tamoxifen-treated mice show degenerative changes in the posterior ventrolateral striatum and the endopiriform claustrum

axon degeneration ( J:260244 )

• motor cortex of tamoxifen-treated mice shows axons of larger caliber displaying Wallerian-like degenerative morphology

dysmyelination ( J:260244 )

• 12-month-old tamoxifen-treated mice exhibit hypomyelinated axons in cortical deep layers, as well as axons with myelin balloons and tuberovesicular structures

• myelination defects preferentially affect axons of larger caliber, with reduced periodicity of myelin lamellae in large axons

• similar myelin defects are seen on white matter tracts containing axonal bundles traveling across the striatum

skeleton

lordokyphosis ( J:260244 )

• 16-month-old mice exhibit lordokyphosis when tamoxifen is administered after P21

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Huntington's disease		DOID:12858	OMIM:143100	J:260244