Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.
PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models.
Howard Hughes Medical Institute Molecular Medicine Program, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Genomic Medicine Institute, Lerner Research Institute.
Amanda K
AK
Tilot
Genomic Medicine Institute, Lerner Research Institute.
Mary K
MK
Gaugler
Genomic Medicine Institute, Lerner Research Institute.
Qi
Q
Yu
Genomic Medicine Institute, Lerner Research Institute.
Todd
T
Romigh
Genomic Medicine Institute, Lerner Research Institute.
Wanfeng
W
Yu
Department of Neurosciences.
Robert H
RH
Miller
Howard Hughes Medical Institute Molecular Medicine Program, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Genomic Medicine Institute, Center for Autism, Pediatric Institute.
Thomas W
TW
Frazier
Howard Hughes Medical Institute Molecular Medicine Program, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Genomic Medicine Institute, Lerner Research Institute, Taussig Cancer Institute, Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH 44195, USA, Department of Genetics and Genome Sciences, CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA engc@ccf.org.
Charis
C
Eng
D000818:Animals; D001921:Brain / Q000503:physiopathology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002659:Child Development Disorders, Pervasive / Q000503:physiopathology*; D003593:Cytoplasm / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D009457:Neuroglia / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction; D012919:Social Behavior
D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse