Activation of endogenous retroviruses characterizes the maternal-fetal interface in the BTBR mouse model of autism spectrum disorder

Abstract

Endogenous retroviruses (ERVs) are genetic elements derived from a process of germline infection by exogenous retroviruses. Some ERVs have been co-opted for physiological functions, and their activation has been associated with complex diseases, including Autism Spectrum Disorder (ASD). We have already demonstrated an abnormal expression of ERVs in the BTBR T + tf/J (BTBR) mouse model of ASD during intrauterine life till adulthood. Thus, starting from the assumptions that ERVs may contribute to the derailment of neurodevelopment and that ASD has fetal origins as a consequence of adverse intrauterine conditions, the present study aims to characterize the transcriptional activity of selected ERVs (MusD, IAP, Syn-A, Syn-B, ARC and GLN), LINE-1, inflammatory mediators (IL-6, IL-10, IL-11 CXCL-1) at the maternal-fetal interface and in dissected embryos from BTBR mice. Our results highlight the deregulation of ERVs and inflammatory mediators at the maternal-fetal interface, and in cephalic and non-cephalic embryonic tissues from BTBR compared to C57BL/6 J. Several correlations among ERV expression levels emerged in different tissues from C57BL/6 J mice while, in BTBR mice, no correlations were found, suggesting that in this model, the acquisition of autistic-like traits might be linked to the dysregulation of ERV activity occurring during intra-uterine life.

Keywords: Autism Spectrum Disorder; BTBR; ERV; Endogenous retroviruses; Inflammation; Maternal–fetal interface.

Fig. 1

Gene expression of MusD, IAP, Syn-A, Syn-B, ARC, GLN, LINE-1 in C57 and BTBR mice. Data are represented as box plots with median value (black horizontal line) and first/third interquartile range. (black *) p < 0.05 or (**) p < 0.001. (*) comparison between mouse strains within each tissue; (red *) comparison between tissues within each mouse strain. For each group, mild and extreme outliers (dots and asterisks, respectively, colored in agreement with the corresponding box plot) are shown. Five BTBR and five C57 dams were sacrificed at gestational day 10.5 and for each tissue: maternal decidua (MD); extra-embryonic tissues (Ee); embryonic cephalic tissues (EC); embryonic non-cephalic tissues (ENC), seven samples were collected.

Fig. 2

Gene expression of IL-6, IL-10, IL-11 and CXCL-1 in C57 and BTBR mice. Data are represented as box plots with median value (black horizontal line) and first/third interquartile range. (black *) p < 0.05 or (**) p < 0.001. (*) comparison between mouse strains within each tissue; (red *) comparison between tissues within each mouse strain. For each group, mild and extreme outliers (dots and asterisks, respectively, colored in agreement with the corresponding box plot) are shown. Five BTBR and five C57 dams were sacrificed at gestational day 10.5 and for each tissue: maternal decidua (MD); extra-embryonic tissues (Ee); embryonic cephalic tissues (EC); embryonic non-cephalic tissues (ENC), seven samples were collected.

Fig. 3

Dissection procedure for tissues recovery. Uterine horns were obtained from GD 10.5 females. For each uterine horn (A), every implantation site (dotted circle) was separated from the others, as in B (dotted circle). Then, for each implantation site (C), myometrial and connective envelope (c1) were dissected and discarded while conceptus (c2), still surrounded by maternal decidual tissues, was retained. In (D), maternal decidua (d1, MD) is shown after separation from the conceptus (d2). In (E), the latter was separated to obtain extra-embryonic (e1, Ee) and embryonic (e2) tissues and finally divided (F) into cephalic (f1, EC) and non-cephalic parts (f2, ENC).