Phenotypes Associated with This Genotype

Genotype
MGI:7284278

• Allelic Composition: Vcp^tm1.1Hiok/Vcp⁺
• Genetic Background: B6(Cg)-Vcp^tm1.1Hiok

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

nervous system

decreased brain weight ( J:308471 )

• in E18 embryos and at age 1 and 3 months

• normal from age 6 months

abnormal cerebral cortex morphology ( J:308471 )

• cytoplasmic ubiquitinated TARDBP aggregates in frontal association cortex and other cortex region neurons at age 6 months

• increased glia cell density in external pyramidal layer of frontal cortex at age 6 months

• increased number of dendrites in external pyramidal layer of frontal cortex at age 6 months

• larger neurons in frontal cortex at age 6 months

• normal in E13 and E15 embryos

abnormal cerebral cortex pyramidal cell morphology ( J:308471 )

• increased number of dendrites in external pyramidal layer of frontal cortex at age 6 months

abnormal stratification in cerebral cortex ( J:308471 )

• thinner layers II-III (CUX1+) and III-V (FOXP1+) at age 6 months

• thicker layer VI (TBR1+) at age 6 months

thin cerebral cortex ( J:308471 )

• in E18 embryos

abnormal frontal lobe morphology ( J:308471 )

• cytoplasmic ubiquitinated TARDBP aggregates in frontal association cortex from age 6 months

• normal in E13 and E15 embryos

abnormal primary motor cortex morphology ( J:308471 )

• cytoplasmic ubiquitinated TARDBP aggregates in M2 motor cortex from age 3 months

decreased dendritic spine number ( J:308471 )

• in layer 1 of dysgranular retrosplenial cortex (RSD) at age 3 months

• increased rate of elimination in layer 1 of dysgranular retrosplenial cortex (RSD) at age 3 months

decreased neuronal stem cell self-renewal ( J:308471 )

• excessive neurogenesis depleting neural stem cells (NSC) pools in ventricular/subventricular zone (VZ/SVZ) in E10 and E15 embryos

behavior/neurological

impaired spatial learning ( J:308471 )

• increased latency to find platform in Morris water maze test from age 6 months

increased anxiety-related response ( J:308471 )

• increased distance traveled in open field test and less time spent in light in light-dark box test from age 6 months

fast extinction of fear memory ( J:308471 )

• impaired fear memory: reduced freezing time in fear-conditioning test from age 12 months

growth/size/body

increased body weight ( J:308471 )

• heavier by age 18 months

microcephaly ( J:308471 )

• developmental microcephaly owing to excessive neurogenesis depleting neural stem cells (NSC) pools in ventricular/subventricular zone (VZ/SVZ) in E10 and E15 embryos

homeostasis/metabolism

abnormal DNA repair ( J:308471 )

• slower DNA damage repair

• accumulation of DNA damage in cerebral cortex at ages 3 and 6 months

• accumulation of DNA damage in differentiated neurons and neural stem cells (NSCs) in cerebral cortex from E13 and E15 embryos

cellular

cellular phenotype ( J:308471 )

N • normal equal and unequal division of cell membranes and mitotic plane angle in apical neural stem/progenitor cells in cerebral cortex of E13 embryos

N • normal apoptosis of differentiating neurons and neural stem cells (NSCs) in forebrains of E15 embryos

abnormal endoplasmic reticulum morphology ( J:308471 )

• ER expansion in cortical neurons

abnormal cell cycle checkpoint function ( J:308471 )

• delayed or arrested G1/S transition in embryonic neural stem cells (NSCs) from cerebral cortex of E15 embryos

• elongated G1 phase and total cell cycle time in neural stem cells (NSCs) from forebrains of E15 embryos

• increase in proportion of proliferating cells exiting cell cycle

• normal M phase time in neural stem cells (NSCs) from forebrains of E15 embryos

• normal M phase transition in ventricular/subventricular zone (VZ/SVZ) of E13 and E15 embryos

cellular necrosis ( J:308471 )

• early-stage transcriptional repression-induced atypical cell death (TRIAD) necrosis of neurons in cerebral cortex from ages 1 to 12 months, peaking at 3 months

abnormal DNA repair ( J:308471 )

• slower DNA damage repair

• accumulation of DNA damage in cerebral cortex at ages 3 and 6 months

• accumulation of DNA damage in differentiated neurons and neural stem cells (NSCs) in cerebral cortex from E13 and E15 embryos

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
frontotemporal dementia		DOID:9255	OMIM:600274	J:308471