Function Of COUP-TFI Gene In Dorsal Hippocampus,and Association With Neural Disease

Human cerebrum is the most hierarchical region in the central nervous system to control cognition,behavior and language.As an important part of the brain,hippocampus is located in the temporal lobe.It is involved in memory encoding and storage.In addition,as part of the limbic system,the dorsal-ventral hippocampus is not only different in the terms of anatomy,but also in function.The dorsal hippocampus is associated with spatial learning and memory,while the ventral hippocampus is associated with emotion.The dysplasia or dysfunction of hippocampus can lead to many neurological diseases,including Alzheimer's disease,depression,autism,schizophrenia and cognitive disorders and so on.We found that the COUP-TFI gene is highly expressed in the primordial of hippocampus during embryogenesis,developing and adult dorsal hippocampus.However,little is known about the function and mechanism of COUP-TFI in the development of hippocampus.COUP-TFI gene mutations result in epilepsy,intellectual disorders,or autism spectrum disorders in human.The studies in mouse have demonstrated that COUP-TFI gene is one of the most important regulatory genes participating in the dorsal telencephalon patterning and the differentiation of cortical projection neurons.However,its role in the development of hippocampus,which originates from medial pallium?MP?in the dorsal telencephalon,is not clear.In this study,by using Emx1Cre mouse,we established the dorsal telencephalon specific COUP-TFI gene conditional knockout(Emx1Cre/+;COUP-TFI^Flox/Flox)mouse successfully.Nissl staining data reveal that dorsal hippocampus is significantly smaller in adult Emx1Cre/+;COUP-TFI^Flox/Floxlox/Flox mutant mice compared to control mice,whereas there is no difference in ventral hippocampus.Compared with the control mice,the cell layer thickness of CA1 area of dorsal hippocampus in mutant mice is thinner obviously,but there is no significant difference in CA3 and DG area.Furthermore,Golgi staining results show that,in the mutant mice,the number of apical and basal dendrites of CA1 projection neurons in dorsal hippocampus are less than that of the control mice significantly,and the density of dendrite spines are increased significantly in CA1 projection neurons of dorsal hippocampus.No matter the number of apical and basal dendrites or the density of dendrite spines of CA1projection neurons in ventral hippocampus,there are no significant difference between mutants and control mice.Behavioral test show that there are no significant difference in the open-field test and the elevated plus mazes test between the mutant mice and the control mice.In the Morris water maze and Barnes maze behavior experiments,the ability of spatial learning and memory in mutant mice is significantly impaired compared with control mice.RNA-seq analysis based on lasar microdissection reveals that in the P28 mutant hippocampus CA1,the expression of a few genes,involved in neuronal synapse and neural development associated diseases,is upregulated.Our study reveals that COUP-TFI gene is not only expressed in primordium of hippocampus,developing and adult hippocampus,but also involved in the maturation of development and function of hippocampus.Our findings will benefit the understanding of the etiolopy of neural development associated diseases such as intellectual disorders,autism spectrum disorders,epilepsy.