title: Abnormal cerebellar development and Purkinje cell defects in Lgl1-Pax2 conditional knockout mice.
abstract: Lgl1 was initially identified as a tumour suppressor in flies and is characterised as a key regulator of epithelial polarity and asymmetric cell division. A previous study indicated that More-Cre-mediated Lgl1 knockout mice exhibited significant brain dysplasia and died within 24h after birth. To overcome early neonatal lethality, we generated Lgl1 conditional knockout mice mediated by Pax2-Cre, which is expressed in almost all cells in the cerebellum, and we examined the functions of Lgl1 in the cerebellum. Impaired motor coordination was detected in the mutant mice. Consistent with this abnormal behaviour, homozygous mice possessed a smaller cerebellum with fewer lobes, reduced granule precursor cell (GPC) proliferation, decreased Purkinje cell (PC) quantity and dendritic dysplasia. Loss of Lgl1 in the cerebellum led to hyperproliferation and impaired differentiation of neural progenitors in ventricular zone. Based on the TUNEL assay, we observed increased apoptosis in the cerebellum of mutant mice. We proposed that impaired differentiation and increased apoptosis may contribute to decreased PC quantity. To clarify the effect of Lgl1 on cerebellar granule cells, we used Math1-Cre to specifically delete Lgl1 in granule cells. Interestingly, the Lgl1-Math1 conditional knockout mice exhibited normal proliferation of GPCs and cerebellar development. Thus, we speculated that the reduction in the proliferation of GPCs in Lgl1-Pax2 conditional knockout mice may be secondary to the decreased number of PCs, which secrete the mitogenic factor Sonic hedgehog to regulate GPC proliferation. Taken together, these findings suggest that Lgl1 plays a key role in cerebellar development and folia formation by regulating the development of PCs.
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Congzhe
authors: C
authors: Hou
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Lingcui
authors: L
authors: Ding
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Jian
authors: J
authors: Zhang
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Yecheng
authors: Y
authors: Jin
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Chen
authors: C
authors: Sun
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Zhenzu
authors: Z
authors: Li
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Xiaoyang
authors: X
authors: Sun
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Tingting
authors: T
authors: Zhang
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China.
authors: Aizhen
authors: A
authors: Zhang
authors: SARITEX Center for Stem Cell Engineering Translational Medicine, Shanghai East Hospital, Shanghai 200123, China; Advanced Institute of Translational Medicine, Tongji University School of Medicine, Shanghai 200123, China; Center for Stem Cell & Nano-Medicine, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 200123, China. Electronic address: huashunli@tongji.edu.cn.
authors: Huashun
authors: H
authors: Li
authors: Key Laboratory of the Ministry of Education for Experimental Teratology and School of Life Science, Shandong University, Jinan 250100, China. Electronic address: jggao@sdu.edu.cn.
authors: Jiangang
authors: J
authors: Gao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002531:Cerebellum / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; C082939:Llgl1 protein, mouse; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D025521:Tumor Suppressor Proteins
keywords: Cerebellar development; Granule cell; Lgl1; Purkinje cells