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PMID:16675393

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Citation

Kwon, CH, Luikart, BW, Powell, CM, Zhou, J, Matheny, SA, Zhang, W, Li, Y, Baker, SJ and Parada, LF (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377-88

Abstract

CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3beta. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.

Links

PubMed Online version:10.1016/j.neuron.2006.03.023

Keywords

Animals; Autistic Disorder/genetics; Autistic Disorder/metabolism; Autistic Disorder/physiopathology; Axons/metabolism; Axons/pathology; Behavior, Animal/physiology; Brain/abnormalities; Brain/metabolism; Brain/physiopathology; Cell Differentiation/genetics; Cerebral Cortex/abnormalities; Cerebral Cortex/metabolism; Cerebral Cortex/physiopathology; Dendrites/metabolism; Dendrites/pathology; Disease Models, Animal; Glycogen Synthase Kinase 3/metabolism; Hippocampus/abnormalities; Hippocampus/metabolism; Hippocampus/physiopathology; Hypertrophy/genetics; Hypertrophy/pathology; Hypertrophy/physiopathology; Mice; Mice, Knockout; Mice, Transgenic; Mutation/genetics; Nervous System Malformations/genetics; Nervous System Malformations/metabolism; Nervous System Malformations/physiopathology; Neurons/metabolism; Neurons/pathology; PTEN Phosphohydrolase/genetics; Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction/physiology; Social Behavior; Startle Reaction/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PTEN

involved_in

GO:0048853: forebrain morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0045792: negative regulation of cell size

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0050771: negative regulation of axonogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0051898: negative regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0061002: negative regulation of dendritic spine morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0035176: social behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0033555: multicellular organismal response to stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0007416: synapse assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

GO:0051898: negative regulation of protein kinase B signaling

ECO:0000315:

P

Pten mutant mice showed increase phosphor-Ser473-Akt (P-Akt) which is a marker for Akt activation in the dentate gyrus. Therefore Pten has a negative regulation role in the PIK3/Akt signalling pathway compared to wild type. Figure 1C.

complete
CACAO 2637

MOUSE:PTEN

GO:0035176: social behavior

ECO:0000315:

P

Control mice exposed to novel mice exhibited typical behaviour of approaching and sniffing (typical social behaviour for mice) but this initial social interaction was decreased in mutant Pten mice, figure 2A. When control mice re-exposed to same mouse, social interaction decreased from initial interaction indicating recognition of familiar mouse showing normal social learning. However this decrease was not seen in mutant mice showing impaired social initial interaction.

Similar result seen in figure 2E. In the test there are two cages one with a adult mouse and another cage with a inanimate object. Control mice spent more time interacting with social target than inanimate target. However Pten mutant mice showed decreased interaction with social target compared to control. Pten mutant mice spent equal amount of time with social target and inanimate target.

Figure 2F, Same result results were in a three roomed chamber. When mice were exposed to novel mouse and familiar mouse, control mouse spend more time with novel mouse than familiar mouse but the Pten mutant mice showed no preference of either novel or familiar mouse figure 2G.

complete
CACAO 2639

MOUSE:PTEN

GO:0030534: adult behavior

ECO:0000315:

P

Figure 2B, control mice showed immediate activity of nest formation but mutant mice showed later nest forming activity.

complete
CACAO 2640

MOUSE:PTEN

GO:0060179: male mating behavior

ECO:0000315:

P

Control male mouse made females pregnant but mutant Pten males did not make female mice pregnant. Figure 2H.

complete
CACAO 2641

MOUSE:PTEN

GO:0042711: maternal behavior

ECO:0000315:

P

When Pten mutant female mice were pregnant and delivered normal size pups, after 5 days the survival rate of pups were decreased in Pten females pups compared to wild type, figure 2H.

complete
CACAO 2642

MOUSE:PTEN

GO:0007626: locomotory behavior

ECO:0000315:

P

Mutant mice showed hyperactivity in more stressful conditions such as being in a bright environment of open field, therefore traveling further and at a increased average speed, figure 3A. But locomotor activity was normal in dark enclosed environment Figure supplementary data 1A and 1B.

complete
CACAO 2643

MOUSE:PTEN

GO:0060134: prepulse inhibition

ECO:0000315:

P

Figure 3B: Pten mutant mice increased initial startle response compared to control. Sensorimotor gating was measured by prepulse inhibition (PPI) paradigm which was impaired in mutant Pten mice compared to control figure 3C

complete
CACAO 2644

MOUSE:PTEN

GO:0007611: learning or memory

ECO:0000315:

P

In Morris water maze, when the platform was submerged, Pten mutant mice did not learn as quickly in terms of time and distance compared to control, figure 3G. In figure 3H, control mice spent more time in target quadrant compared to mutant Pten mice where no preference was shown.

complete
CACAO 2645

MOUSE:PTEN

GO:0001966: thigmotaxis

ECO:0000315:

P

In the Morris water maze, mutant Pten mice showed to swim more long the edge of the maze which was also seen in the open field test compared to control, figure 3I.

complete
CACAO 2646

MOUSE:PTEN

GO:0048853: forebrain morphogenesis

ECO:0000315:

P

Mutant Pten mice showed progressive macrocephaly (abnormal large head) compared to control (figure 4A). Progressive macrocephaly was seen in the forebrain area (cortex and hippocampus figure 4b and C)

complete
CACAO 2647

MOUSE:PTEN

GO:0045792: negative regulation of cell size

ECO:0000315:

P

Supplementary figure S2A-C shows that aging mice as increase in soma hypertrophy of Pten mutant mice compared to control.

complete
CACAO 2648

MOUSE:PTEN

GO:0021955: central nervous system neuron axonogenesis

ECO:0000315:

P

Figure 5A showed abnormal axonal processes in mutant Pten mice compared to control. Also figure 5B shows abnormal axonal projection in dentate gyrus mossy fiber tracts. Adult mutant Pten mice showed enlargement of mossy fiber tract (supplementary figure 3A and B)

complete
CACAO 2649

MOUSE:PTEN

GO:2000808: negative regulation of synaptic vesicle clustering

ECO:0000315:

P

Figure 5C shows Pten mutant mice had increase presynaptic vesicles compared to control.

complete
CACAO 2650

MOUSE:PTEN

GO:0061002: negative regulation of dendritic spine morphogenesis

ECO:0000315:

P

Figure 6A, showed 3 month old mutant Pten mice had thickened elongated processes. Also dendritic hypertrophy seen in adult mutant Pten mice in the dentate gyrus, figure 6B. Also figure 6C shows increase of 24.9% in dendritic spine density in mutant Pten mice compared to control mice.

complete
CACAO 2651

MOUSE:PTEN

involved_in

GO:0030534: adult behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0042711: maternal behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0007626: locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0060134: prepulse inhibition

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:2000808: negative regulation of synaptic vesicle clustering

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0021955: central nervous system neuron axonogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0007611: learning or memory

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTEN

involved_in

GO:0060179: male mating behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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