Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression
Abstract Genetic studies in ASD have mostly focused on the proband, with no clear understanding of parental genetic contributions to fetal neurodevelopment. Among parental etiological factors, perinatal maternal inflammation secondary to autoimmunity, infections, and toxins is associated with ASD. H...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-06-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-021-01472-x |
| _version_ | 1818899896493670400 |
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| author | Ritika Jaini Matthew R. Wolf Qi Yu Alexander T. King Thomas W. Frazier Charis Eng |
| author_facet | Ritika Jaini Matthew R. Wolf Qi Yu Alexander T. King Thomas W. Frazier Charis Eng |
| author_sort | Ritika Jaini |
| collection | DOAJ |
| description | Abstract Genetic studies in ASD have mostly focused on the proband, with no clear understanding of parental genetic contributions to fetal neurodevelopment. Among parental etiological factors, perinatal maternal inflammation secondary to autoimmunity, infections, and toxins is associated with ASD. However, the inherent impact of maternal genetics on in-utero inflammation and fetal neurodevelopment in the absence of strong external inflammatory exposures is not known. We used the Pten WT/m3m4 mouse model for ASD to demonstrate the impact of maternal genetics on the penetrance of ASD-like phenotypes in the offspring. Pten WT/m3m4 (Momm3m4) or Pten WT/WT (MomWT) females, their offspring, and placental interface were analyzed for inflammatory markers, gene expression, and cellular phenotypes at E17.5. Postnatal behavior was tested by comparing pups from Momm3m4 vs. MomWT. Mothers of the Pten WT/m3m4 genotype (Momm3m4) showed inadequate induction of IL-10 mediated immunosuppression during pregnancy. Low IL-10 in the mother was directly correlated with decreased complement expression in the fetal liver. Fetuses from Momm3m4 had increased breakdown of the blood–brain–barrier, neuronal loss, and lack of glial cell maturation during in-utero stages. This impact of maternal genotype translated to a postnatal increase in the risk of newborn mortality, visible macrocephaly and ASD-like repetitive and social behaviors. Depending on maternal genotype, non-predisposed (wildtype) offspring showed ASD-like phenotypes, and phenotypic penetrance was decreased in predisposed pups from MomWT. Our study introduces the concept that maternal genetics alone, without any added external inflammatory insults, can modulate fetal neurodevelopment and ASD-related phenotypes in the offspring via alteration of IL-10 mediated materno-fetal immunosuppression. |
| first_indexed | 2024-12-19T19:55:15Z |
| format | Article |
| id | doaj.art-b5775fc5c3b14be386f1c88486d9d8dc |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-19T19:55:15Z |
| publishDate | 2021-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-b5775fc5c3b14be386f1c88486d9d8dc2022-12-21T20:07:50ZengNature Publishing GroupTranslational Psychiatry2158-31882021-06-0111111410.1038/s41398-021-01472-xMaternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppressionRitika Jaini0Matthew R. Wolf1Qi Yu2Alexander T. King3Thomas W. Frazier4Charis Eng5Genomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicAbstract Genetic studies in ASD have mostly focused on the proband, with no clear understanding of parental genetic contributions to fetal neurodevelopment. Among parental etiological factors, perinatal maternal inflammation secondary to autoimmunity, infections, and toxins is associated with ASD. However, the inherent impact of maternal genetics on in-utero inflammation and fetal neurodevelopment in the absence of strong external inflammatory exposures is not known. We used the Pten WT/m3m4 mouse model for ASD to demonstrate the impact of maternal genetics on the penetrance of ASD-like phenotypes in the offspring. Pten WT/m3m4 (Momm3m4) or Pten WT/WT (MomWT) females, their offspring, and placental interface were analyzed for inflammatory markers, gene expression, and cellular phenotypes at E17.5. Postnatal behavior was tested by comparing pups from Momm3m4 vs. MomWT. Mothers of the Pten WT/m3m4 genotype (Momm3m4) showed inadequate induction of IL-10 mediated immunosuppression during pregnancy. Low IL-10 in the mother was directly correlated with decreased complement expression in the fetal liver. Fetuses from Momm3m4 had increased breakdown of the blood–brain–barrier, neuronal loss, and lack of glial cell maturation during in-utero stages. This impact of maternal genotype translated to a postnatal increase in the risk of newborn mortality, visible macrocephaly and ASD-like repetitive and social behaviors. Depending on maternal genotype, non-predisposed (wildtype) offspring showed ASD-like phenotypes, and phenotypic penetrance was decreased in predisposed pups from MomWT. Our study introduces the concept that maternal genetics alone, without any added external inflammatory insults, can modulate fetal neurodevelopment and ASD-related phenotypes in the offspring via alteration of IL-10 mediated materno-fetal immunosuppression.https://doi.org/10.1038/s41398-021-01472-x |
| spellingShingle | Ritika Jaini Matthew R. Wolf Qi Yu Alexander T. King Thomas W. Frazier Charis Eng Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression Translational Psychiatry |
| title | Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression |
| title_full | Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression |
| title_fullStr | Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression |
| title_full_unstemmed | Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression |
| title_short | Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression |
| title_sort | maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder like phenotype by modulating in utero immunosuppression |
| url | https://doi.org/10.1038/s41398-021-01472-x |
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