Department of Biosignals and Inheritance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan; Department of Medicine and Science in Sports and Exercise, Tohoku University School of Medicine, Sendai 980-8575, Japan.
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Cell Rep. 2024 Oct 22;43(10):114789. doi: 10.1016/j.celrep.2024.114789. Epub 2024 Sep 25.
Offspring growth requires establishing maternal behavior associated with the maternal endocrine profile. Placentae support the adaptations of the mother, producing bioactive molecules that affect maternal organs. We recently reported that placentae produce superoxide dismutase 3 (SOD3) that exerts sustained effects on the offspring liver via epigenetic modifications. Here, we demonstrate that placenta-specific Sod3 knockout (Sod3) dams exhibited impaired maternal behavior and decreased prolactin levels. Most fibroblast growth factor (FGF)-regulated pathways were downregulated in the pituitary tissues from Sod3 dams. FGF1-, FGF2-, and FGF4-induced prolactin expression and signaling via the phosphoinositide 3-kinase (PI3K)-phospholipase C-γ1 (PLCγ1)-protein kinase-Cδ (PKC)δ axis were reduced in primary pituitary cells from Sod3 dams. Mechanistically, FGF1/FGF receptor (FGFR)2 expressions were inhibited by the suppression of the ten-eleven translocation (TET)/isocitrate dehydrogenase (IDH)/α-ketoglutarate pathway and DNA demethylation levels at the zinc finger and BTB domain containing 18 (ZBTB18)-targeted promoters of Fgf1/Fgfr2. Importantly, offspring from Sod3 dams also showed impaired nurturing behavior to their grandoffspring. Collectively, placenta-derived SOD3 promotes maternal behavior via epigenetic programming of the FGF/FGFR-prolactin axis.
后代的生长需要建立与母体内分泌特征相关的母性行为。胎盘支持母亲的适应，产生影响母体器官的生物活性分子。我们最近报道胎盘产生超氧化物歧化酶 3（SOD3），通过表观遗传修饰对后代肝脏产生持续影响。在这里，我们证明胎盘特异性 Sod3 敲除（Sod3）母鼠表现出母性行为受损和催乳素水平降低。大多数成纤维细胞生长因子（FGF）调节途径在 Sod3 母鼠的垂体组织中下调。FGF1、FGF2 和 FGF4 通过磷酸肌醇 3-激酶（PI3K）-磷脂酶 C-γ1（PLCγ1）-蛋白激酶 Cδ（PKCδ）轴诱导催乳素表达和信号转导在 Sod3 母鼠的原代垂体细胞中减少。从机制上讲，FGF1/FGFR（FGFR）2 的表达受到抑制，因为 TEN-ELVEN 转位（TET）/异柠檬酸脱氢酶（IDH）/α-酮戊二酸途径和锌指和 BTB 结构域包含 18（ZBTB18）-靶向 Fgf1/Fgfr2 启动子的 DNA 去甲基化水平受到抑制。重要的是，Sod3 母鼠的后代也表现出对其孙代的养育行为受损。总之，胎盘源性 SOD3 通过 FGF/FGFR-催乳素轴的表观遗传编程促进母性行为。
