Phenotypes associated with this allele

• Allele Symbol: Lmx1a^tm1Tpe
• Allele Name: targeted mutation 1, Thomas Perlmann
• Allele ID: MGI:5287978
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Lmx1a^tm1Tpe/Lmx1a^tm1Tpe Lmx1b^tm1Zfc/Lmx1b^tm1Zfc Slc6a3^tm1(cre)Lrsn/Slc6a3^+	involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/SvJ * C57BL/6	MGI:5647883
cn2	Lmx1a^tm1Tpe/Lmx1a^tm1Tpe Lmx1b^tm1Zfc/Lmx1b^tm1Zfc Tg(Slc6a3-cre/ERT2)1Span/0	involves: 129S7/SvEvBrd * C57BL/6	MGI:5647909

Genotype
MGI:5647883

cn1

• Allelic Composition: Lmx1a^tm1Tpe/Lmx1a^tm1Tpe; Lmx1b^tm1Zfc/Lmx1b^tm1Zfc; Slc6a3^tm1(cre)Lrsn/Slc6a3⁺
• Genetic Background: involves: 129S1/Sv * 129S7/SvEvBrd * 129X1/SvJ * C57BL/6

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

behavior/neurological

impaired short-term object recognition memory ( J:222854 )

• novel object recognition test indicates impaired short-term memory formation in adult and aged mice

• however, no differences are seen in anxiety or depression-like tests

impaired coordination ( J:222854 )

• impaired motor coordination in the pole test at 6 months of age and in the beam traversal and pole test at 18 months of age

increased locomotor activity ( J:222854 )

• in the open field, mice show a modest increase in locomotor activity at 18, but not 6, months of age

nervous system

abnormal innervation ( J:222854 )

• midbrain dopamine neuron innervation is impaired

• treatment with rapamycin almost completely normalizes the reduced striatal TH innervation

abnormal synaptic bouton morphology ( J:222854 )

• 3 month old mice exhibit abnormal nerve terminals in the striatum, with a 50% reduction in the density of TH-positive nerve terminals and abnormally large nerve terminals that reach up to 22 um in diameter frequently throughout the dorsal and ventral striatum

• enlarged presynaptic boutons show fewer synaptic vesicles at active zones and are filled with vacuoles and multilamellar autophagic-lysosomal vesicles that sometimes contain mitochondria

• 23% lower occurrence of synaptic active zones

• treatment with rapamycin alleviates the occurrence of abnormally large TH+ boutons in the striatum

abnormal synapse morphology ( J:222854 )

• synaptic morphology is disrupted in presynaptic midbrain dopamine neuron terminals

abnormal synaptic vesicle number ( J:222854 )

• enlarged presynaptic boutons show fewer synaptic vesicles at active zones

neurodegeneration ( J:222854 )

• progressive loss of TH-positive neurons in the ventral midbrain, with degenerating TH+ neurons frequently seen in young mice; reduction is seen within both the dorsal and ventral striatum

• dopamine transporter (DAT) expression is reduced, showing a modest reduction in young mice but a significant reduction in aged mice, indicating dopaminergic neuron degeneration

enhanced long-term potentiation ( J:222854 )

• mice exhibit enhanced induced LTP of Shaffer collateral-CA1 pyramidal cell synapses

• however, basal synaptic transmission is normal

taste/olfaction

impaired olfaction ( J:222854 )

• social olfaction is impaired in adult (6 months) and aged (18 months) mice

cellular

abnormal lysosome morphology ( J:222854 )

• accumulation of lysosomes in axonal terminals of midbrain dopamine neurons

abnormal autophagy ( J:222854 )

• accumulation of autophagosomes in axonal terminals of midbrain dopamine neurons

abnormal lysosome physiology ( J:222854 )

• the number of lipofuscin granules are reduced in midbrain dopamine neurons

• accumulation of electron-dense protein aggregates in midbrain dopamine neuron cell bodies

homeostasis/metabolism

abnormal autophagy ( J:222854 )

• accumulation of autophagosomes in axonal terminals of midbrain dopamine neurons

decreased dopamine level ( J:222854 )

• dopamine and its metabolites are reduced in brain areas such as prefrontal cortex, hippocampus, dorsal striatum, nucleus accumbens, substantia nigra and the ventral tegmental area

• however, levels are not reduced in the olfactory bulb or the cerebellum

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:222854

Genotype
MGI:5647909

cn2

• Allelic Composition: Lmx1a^tm1Tpe/Lmx1a^tm1Tpe; Lmx1b^tm1Zfc/Lmx1b^tm1Zfc; Tg(Slc6a3-cre/ERT2)1Span/0
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

nervous system

abnormal synaptic bouton morphology ( J:222854 )

• abnormally enlarged nerve terminals are seen in mice 4 weeks after treatment with tamoxifen at 4 weeks of age, showing fewer synaptic vesicles at active zones and an increase in the number of autophagic-lysosomal vesicles

neurodegeneration ( J:222854 )

• striatal expression of dopamine transporter (DAT) is reduced in the ventral striatum 18 months after tamoxifen treatment indicating dopaminergic neuron loss, however, no loss of TH or DAT expression in the dorsal striatum and no loss of TH+ cells are seen at this time point

homeostasis/metabolism

decreased dopamine level ( J:222854 )

• dopamine and its metabolites are diminished after tamoxifen treatment of 4 week old mice