The Function Of LGL1 In Olfactory Bulb Development

Scientific questions to be solvedIn this paper, we generatedLGL1 conditional knockout mice by the Cre-LoxP system, Pax2-LGL1 knockout mice in OB to study the function of the LGLl gene in the OB in mice. The scientific issues to be solved are as follows:(1) the function of LGL1 in the development of OB in mice;(2) the possible mechanism of LGL1 in the regulation of the olfaction; (3) the molecular mechanism of LGL1 in the regulation of migration and orientation of neurons in OB in mice.Research programs and resultsIn this thesis, to solve the scientific tissues mentioned above, we we generated LGL1 conditional knockout mice by the Cre-LoxP system (Pax2-LGL1 conditional knockout mice), generated by crossing LGLlLoxP/LoxP mice with Pax2-Cre transgene mice. We studied the function and molecular mechanism of LGL1 gene in the development of OB and olfaction.The Pax2-LGL1 conditional knockout mice expressed Cre recombinase in the OB at E7.5, and the LGL1 mutant mice can survive to adult. In our study, we found that the Lgll conditional mutants exhibited abnormal morphological characteristics of the OB: dorsal surface area of the OB of Lgll mutants was significantly smaller than wild type (WT). There was also a significant difference in average weight between mutant mice and WT:decrease of litter size in both females and males in mutant mice. Our behavioral analysis exhibited greatly impaired olfaction in Lgll mutant mice.To test the variation of olfaction caused by deficiency of LGL1, behavioral tests were performed using the buried food pellet recovery test and the olfaction maze test. The latency times were significantly greater for the LGL1 mutants than WT both in food pellet recovery test and the olfaction maze test, indicating the impaired olfaction in 'LGL1 mutant mice.As described previously, the laminated structure of OB is conservative relatively, and neurons are organized into distinct layers. In the study, the OB in Lgll mutants seemed disorganized, no obvious distinctions between the laminar structures, and the flatted glomerular layer (GL) and thinner mitral cell layer (MCL). The neurons of glomeruli appeared to only be stacked on top and loss of mitral cells (MCs) in MCL observed in LGL1 mutant mice.Sp8, used to identify specific interneurons population of OB, is one member of the Spl zinc-finger transcription factor gene family. In this research, we investigated the changes in SP8+ interneurons in the GL, to determine the consequences of Lgll deletion on SP8+ interneuron formation of GL and there was an obvious decrease of SP8+ interneurons in the GL in the LGL1 mutant mice.In odor information process, MCs in MCL receive the signal inputs from OSNs at glomeruli, and then send output to cortical areas. To confirm the changes in MCL thickness and the number of MCs caused by deficiency of LGL1 in mutant mice, we performed study on MCL thickness and the number of MCs, the results indicated MCL was significantly thinner in mutant mice than WT, and the number of MCs was significantly lower in LGL1 mutant mice than WT. It has been reported that the role of LGL1 in the regulation of cell migration and hyper proliferation, the results indicated that LGL1 might play a crucial role in maintaining the normal morphologyby impacting levels of MCs.SignificanceIn this thesis, we clarified the important role of the LGL1 gene in the OB development and olfaction in mouse using Pax2-LGL1 conditional knockout mice. At the molecular and cellular level, we also studied the possible mechanisms of LGL1 in developmental of OB and the affection on the migration of interneurons and projection neurons of OB, which provide a theoretical basis for the further study of nervous system in higher animals. In addition, as the degree of social population aging increases, the nervous degenerative disease, especially the AD, becomes more and more popular, and it has not found the real effective cure in the area of medical. For the nature of the olfactory dysfunction associated with AD and difficulty in identifying odors predicting subsequent development of mild cognitive impairment (MCI), The research on the development of OB and olfaction, it would promote the development of neuropathic disease clinical diagnosis and treatment to some extent, for example, AD.In this paper, using the Cre-LoxP system, we generated LGL1 conditional knockout mice surviving to adult, which provide a ideal animal model of human disease. It would not only provide the theoretical basis for clinical diagnosis and treatment, but also provide new ideas for treatment of the cognitive impairment in higher animals. From in patients with neurological disease, especially AD, to detect whether the possible mutation of LGL1 gene, would provide design on drugs targeted site and theoretical basis for nerve-related diseases treatment. Therefore, the results in our research would not only provide the basic research of the development of OB, but also to a certain extent promoted the research on olfactory dysfunction and clinical diagnosis and treatment of related neurological disease.