title: LKB1 Regulates Cerebellar Development by Controlling Sonic Hedgehog-mediated Granule Cell Precursor Proliferation and Granule Cell Migration.
abstract: The Liver Kinase B1 (LKB1) gene plays crucial roles in cell differentiation, proliferation and the establishment of cell polarity. We created LKB1 conditional knockout mice (LKB1(Atoh1) CKO) to investigate the function of LKB1 in cerebellar development. The LKB1(Atoh1) CKO mice displayed motor dysfunction. In the LKB1(Atoh1) CKO cerebellum, the overall structure had a larger volume and more lobules. LKB1 inactivation led to an increased proliferation of granule cell precursors (GCPs), aberrant granule cell migration and overproduction of unipolar brush cells. To investigate the mechanism underlying the abnormal foliation, we examined sonic hedgehog signalling (Shh) by testing its transcriptional mediators, the Gli proteins, which regulate the GCPs proliferation and cerebellar foliation during cerebellar development. The expression levels of Gli genes were significantly increased in the mutant cerebellum. In vitro assays showed that the proliferation of cultured GCPs from mutant cerebellum significantly increased, whereas the proliferation of mutant GCPs significantly decreased in the presence of a Shh inhibitor GDC-0049. Thus, LKB1 deficiency in the LKB1(Atoh1) CKO mice enhanced Shh signalling, leading to the excessive GCP proliferation and the formation of extra lobules. We proposed that LKB1 regulates cerebellar development by controlling GCPs proliferation through Shh signalling during cerebellar development.
authors.affiliation: School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Men
authors.affiliation: School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Zhang
authors.affiliation: School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.
authors.forename: Haixiang
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.
authors.forename: Yecheng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Sun
authors.affiliation: SARITEX Center for Stem Cell, Engineering Translational Medicine, Shanghai East Hospital, 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.|Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, Guangdong, China.
authors.forename: Huashun
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Gao
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D038081:Organogenesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases