Role And Mechanism Of Tet1 In Cognition Of Offspring With Fetal Growth Restriction

Fetal growth restriction(FGR)refers to that the fetus does not reach its full genetic growth potential in the uterus due to the adverse factors.It affects approximately 5% of all newborns.FGR is not only the second leading cause of perinatal morbidity and mortality but also strongly linked to neurodevelopmental disorders later in life.Numerous large-scale follow-up studies have proved that children and adolescents born with FGR have learning difficulties and memory impairments,such as poorer spatial memory,lower academic achievements,and a lower intelligence quotient.In the mammalian hippocampus,neural stem cells(NSCs)located in the subgranular zone(SGZ)of the dentate gyrus(DG)proliferate and differentiate into neurons and astrocytes,and these neurons integrate into the existing circuitry.This process known as neurogenesis occurs during early development,persists throughout life and it is vital for cognitive processes,such as learning and memory.One hallmark of neurogenesis is its dynamic regulation by various physiological and pathological stimuli,such as exercise,aging,and stress.Currently,studies involving animal models of FGR have revealed reduced neuron numbers,abnormal morphology and altered connectivity in the hippocampus.Therefore,understanding how FGR affects hippocampal neurogenesis is beneficial to intervention and treatment of related cognitive disorders.This thesis studied the role of Tet1 in regulating hippocampal neurogenesis and cognitive deficits in the offspring of FGR and its regulatory mechanism.In this study,based on methods reported in the literature,we established two FGR mouse models,including exposure to glucocorticoids(GC)to mimic the mother’s chronic stress or excessive GC treatment(DEX-FGR)and prenatal protein restriction to represent maternal undernutrition(PR-FGR).Firstly,we found that the hippocampusdependent learning and memory of FGR mice have defects in adulthood through novel object recognition test,Morris water maze test and contextual fear conditioning test.Secondly,immunofluorescence staining showed that the proliferation of hippocampal NSC was decreased,and it leads to a decrease in the number of neurons and hippocampal neurogenesis in FGR mice compare to normal mice.We further found that the expression of Tet1 in the hippocampus of FGR mice continued to decrease from early postnatal to adulthood.In addition,RNA-seq revealed the long-term transcriptional inhibition of the Notch signaling in FGR mice.Ch IP-q PCR,h Me DIPq PCR and bisulfite sequencing analysis found that the down-regulation of Tet1 in the hippocampus of FGR mice reduced its enrichment in the Dll3 and Notch1 promoter regions,resulting in hypermethylation in the promoter regions of Dll3 and Notch1 and the decrease of the expression of Notch signaling genes.Thereby,it leads to a reduce in the proliferation of hippocampal NSC and defects in learning and memory.Overexpression of Tet1 via bilateral stereotactic injections of retrovirus into the hippocampal DG activated the Notch signaling pathway,promoted the proliferation of hippocampal NSC in FGR mice and improved the hippocampus-dependent learning and memory impairment.In summary,our study found that the hippocampal-dependent learning and memory abilities of FGR adult offspring are impaired,the proliferation of hippocampal NSC and neurogenesis is reduced.FGR leads to the decrease of Tet1 expression,which reduces its enrichment at the promoter region of the key molecule of the Notch signaling pathway and leads to hypermethylation of these regions and inhibits gene transcription.The persistence of decreased Tet1/Notch signaling pathway continuously inhibits hippocampal neurogenesis and impairs cognition in FGR offspring.Our research provides potential new molecular targets for the intervention and treatment of learning and memory disorders in FGR offspring.