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Maternal Genetics Influences Fetal Neurodevelopment and Postnatal Jaini et al. Translational Psychiatry (2021) 11:348 https://doi.org/10.1038/s41398-021-01472-x Translational Psychiatry ARTICLE Open Access Maternal genetics influences fetal neurodevelopment and postnatal autism spectrum disorder-like phenotype by modulating in-utero immunosuppression Ritika Jaini 1,2, Matthew R. Wolf1,QiYu1, Alexander T. King1,ThomasW.FrazierJr. 1,3,4 and Charis Eng 1,2,5 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 PtenWT/m3m4 mouse model for ASD to demonstrate the impact of maternal genetics on the penetrance of ASD-like phenotypes in the offspring. PtenWT/m3m4 (Momm3m4)orPtenWT/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 PtenWT/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. m3m4 – – 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Fetuses from Mom 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. Introduction of the disorder2,3 including concordance in monozygotic Autism spectrum disorder (ASD) affects 1 in 54 chil- twins4,5. In spite of strong evidence for a genetic etiology, dren in the United States and imposes major health, approximately 80% of ASD cannot be explained by – societal and economic burdens1. The etiology of ASD is monogenic mutations or copy number variants (CNVs)6 multifactorial and complex. Genetic contributions to the 9. Even in monogenic ASD, penetrance is almost never – etiology of ASD are well established with high heritability complete10 13. Therefore, the risk architecture of ASD is thought to involve additive effects of multiple genetic mutations/single-nucleotide polymorphisms (SNPs) or Correspondence: Charis Eng ([email protected]) CNVs as well as environmental factors, mostly of low 1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, penetrance that act in combination to overcome the Cleveland, OH 44195, USA threshold of clinical phenotype development. 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA Full list of author information is available at the end of the article © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Jaini et al. Translational Psychiatry (2021) 11:348 Page 2 of 14 ASD genetics has been predominantly focused on the Materials and methods proband in order to identify specific pathological Mice WT/m3m4 pathways responsible for the neurological and behavioral All experiments were performed on the Pten phenotypes10. Few studies focus on parental genetics in knock-in mutant model generated on the C57Bl/6 back- WT/m3m4 ASD, and to date, have failed to identify significant ground as described previously42,43. Pten germ- associations with ASD in the offspring. Parental line mutations restrict Pten expression to the cytoplasm, SNPs/CNVs highlighted in some studies are often resulting in a constitutive decrease in total Pten protein WT/WT m3m4/m3m4 located in the vicinity of, or within, ASD-associated compared to Pten . Pten homozygous – WT/m3m4 genes14 16. mutations are embryonic lethal. All Pten females WT/WT Increased risk of ASD in mothers with auto- used for breeding were derived from Pten dams. – immunity17 19, high disease concordance in sib- Breeding pairs were set at 7–8 weeks of age for both lings20,21 as well as increased incidence of ASD on genders. Mice underwent gestation in similarly controlled – perinatal exposure to pathogens or toxins22 25 may all colony conditions till E17.5 or full term as per the converge on fetal exposure to maternal inflammation as experimental design. the causative factor (reviewed in refs. 26,27). Increasing numbers of studies suggest an in-utero gestational Animal ethics statement etiology for ASD28,29. Although human studies are All procedures were approved by the Cleveland Clinic’s mostly associative, murine studies have established the Institutional Animal Care and Use Committee under role of maternal inflammation in ASD by experimental protocol numbers 2018-1952 and 2017-1879 and guided injection of strong inflammatory mediators, such as by the Principles of Laboratory Animal Care formulated IgG, LPS, or Poly I:C during pregnancy, isolated from by the National Society for Medical Research. – other confounding factors30 34. Maternal genetics may be an important modulator of this in-utero inflamma- Behavior analysis tion. Few immune response-related genes have been Three chamber sociability (n = 10), distance traveled (n suggested to confer a high risk of having offspring with = 9), and marble burying (n = 10) tests were performed as – ASD35 37. However, the inherent impact of maternal described previously42,44. genetics on ASD pathogenesis during in-utero neuro- development, in the absence of strong pro- Measurement of macrocephaly inflammatory insults or ongoing inflammation is not Macrocephaly was visually assessed at ages P2–P40 by understood. Moreover, the processes by which maternal an investigator blinded to the maternal/pup genotype. genetics may modulate the penetrance of high-risk Brains were weighed immediately post-dissection at P40. monogenic ASD genes in genetically predisposed Coronal brain sections, in the same plane anterior to the offspring have not been demonstrated. Here we hippocampus, were measured for length (L) and breadth aim to demonstrate the inherent role of maternal (B) using Image J software. Area was calculated assuming genetics predisposing to inflammation, on in-utero an ellipse as π(L/2 × B). neurodevelopment using a Pten mutant murine model for ASD. Multiplex bead-based cytokine assays PTEN is ranked as a category-1 (i.e., high-confidence) Serum (1:2 dilution) and uterine fluid (no dilution) were ASD-associated gene (SFARI database11,38. PTEN tested using the mouse high sensitivity T-cell magnetic germline mutations account for as much as 2% of all bead panel and the mouse cytokine/chemokine bead ASD and 17% of macrocephalic-ASD39. The biological panel as per manufacturer’s instructions (Millipore, impact of PTEN function on neurodevelopment is Billerica, MA). reflected in the fact that 95% of patients with germline PTEN mutations have macrocephaly caused mainly by Enzyme-linked immunosorbent assay (ELISA) megalencephaly, and clear white matter abnormalities An antiphospholipid antibody, TGFβ2, and GDF-15 in the brain40,41. With an approximately 23% pene- ELISAs were performed on maternal sera, uterine fluid or trance of ASD, PTEN germline mutations provide a fetal liver at gestational day E17.5 according to manu- good genetic model system to study the additional facturer instructions (Supplementary Table 1). Absor- impact of environmental and genetic modifiers that bance was measured at 450 nm on a SynergyMx help overcome the threshold for phenotype develop- Microplate reader (BioTek, Winooski, VT). ment. We used our Pten mutant murine model for ASD m3m4 (Pten ), to elucidate the impact of maternal genetics Immunohistochemistry/immunofluorescence on the development and modulation of PTEN-ASD like Immunohistochemistry (IHC) staining was performed phenotype in genetically high-risk offspring. as previously described for frozen sections45. Primary and Jaini et al. Translational Psychiatry (2021) 11:348 Page 3 of 14 secondary (HRP or florescent labeled) antibodies were size was determined based on our previous studies uti- acquired commercially
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