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planar cell polarity genes, Celsr1-3, in neural development

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Neuroscience Bulletin 2012年第3期28卷 309-315页

作者： Jia Feng Qi Han Libing Zhou Joint Laboratory for Brain Function and Health Jinan University and The University of Hong KongMedical School of Jinan UniversityGuangzhou 510632China

flamingo is among the ＇core＇ planar cell-polarity genes, protein of which belongs to a unique cadherin subfamily. In contrast to the classic cadherins, composed of several extracellular cadherin repeats, one transmembrane domain and one cytoplasmic segment linked to catenin binding, Drosophila Flamingo has seven transmembrane segments and a cytoplasmic tail with no catenin-binding sequence. In Drosophila, Flamingo has pleotropic roles in controlling epithelial polarity and neuronal morphogenesis. Three mammalian orthologs of flamingo, Celsrl-3, are widely expressed in the nervous system. Recent work has shown that Celsrl-3 play important roles in neural development, such as in axon guidance, neuronal migration, and cilium polarity. CeIsrl-3 single-gene knockout mice exhibit different phenotypes, but there are cooperative interactions among these genes.

关键词： planar cell polarity Celsr genes neural development

Disruption of planar cell polarity Pathway Attributable to Valproic Acid-Induced Congenital Heart Disease through Hdac3 Participation in Mice

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Chinese Medical Journal 2018年第17期131卷 2080-2088页

作者： Hong-Yu Ouan Kai-Yu Zhou Tao Wang Yi Zhang Yi-Fei Li Yi-Min Hua Chuan Wang Department of Pediatric Cardiology West China Second University Hospital Sichuan University Chengdu Sichuan 610041 China Cardiac Development and Early Intervention Unit West China Institute of Women and Children's Health West China Second University Hospital Sichuan University Chengdu Sichuan 610041 China Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) Ministry of Education Chengdu Sichuan 610041 China Key Laboratory of Development and Diseases of Women and Children of Sichuan Province West China Second University Hospital Sichuan University Chengdu Sichuan 610041 China

Background： Valproic acid （VPA） exposure during pregnancy has been proven to contribute to congenital heart disease （CHD）. Our previous findings implied that disruption of planar cell polarity （PCP） signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase （HDAC） inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes （Vangl2/Scrib/Rac 1）, subsequently screening out the specific HDACs regulating PCP pathway. Methods： VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day ! 0.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells （undifferentiated rat cardiomyoblasts） were transfected with Hdac1/2/3 specific small interfering RNA （siRNA）. Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Racl mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric ***： VPA could induce CHD （P 〈 0.001） and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression （all P 〈 0.05）. In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression （P 〈 0.01 ）, while knockdown of Hdac 1/2 had no influence （P 〉 0.05）, VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity （P 〈 0.01 ）, while overexpression of Hdac3 could rescue the VPA-induced inhibition （P 〉 0.05）. Conclusion： VPA could inhibit Hdac1/2/3, Vang12/Sc

关键词： Congenital Heart Disease Hdacs planar cell polarity Valproic Acid

Genetic evidence in planar cell polarity signaling pathway in human neural tube defects

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Frontiers of Medicine 2014年第1期8卷 68-78页

作者： Chunquan Cai Ouyan Shi Department of Surgery Tianjin Children's Hospital Tianjin 300074 China School of Basic Medical Sciences Tianjin Medical UniversityTianjin 300070 China

Neural tube defects （NTDs） are a group of birth anomalies having a profound physical, emotional, and financial effects on families and communities. Their etiology is complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. The planar cell polarity （PCP） pathway controls the process of convergent extension （CE） during gastrulation and neural tube closure and has been implicated in the pathogenesis of NTDs in animal models and human cohorts. This review summarizes the cumulative results of recent studies on PCP signaling pathway and human NTDs. These results demonstrate that PCP gene alterations contribute to the etiology of human NTDs.

关键词： planar cell polarity neural tube defects rare mutations

Loss of liver kinase B1 causes planar polarity defects in cochlear hair cells in mice

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Frontiers of Medicine 2016年第4期10卷 481-489页

作者： Yuqin Men Aizhen Zhang Liwen Zhang Yecheng Jin Zhishuo Wang Jing Zhao Xiaolin Yu Jian Zhang Jiangang Gao Sehool of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology Shandong University Jinan 250100 China jinan First People's Hospital Jinan 250011 China

The tumor suppressor gene liver kinase B1 （LKB1）, also called STKll, encodes a serine/threonine kinase. LKB1 plays crucial roles in cell differentiation, proliferation, and polarity. In this study, LKB1 conditional knockout mice （LKB1pax2 CKO mice） were generated using Pax2-Cre mice to investigate the function of LKB1 in inner ear hair cells during early embryonic period. LKB1Pax2 CKO mice died perinatally. Immunofluorescence and scanning electron microscopy revealed that stereociliary bundles in LKB1Pax2 CKO mice were clustered and misoriented, respectively. Moreover, ectopic distribution of kinocilium bundles resulting from abnormal migration of kinocilium was observed in the mutant mice. The orientation of stereociliary bundles and the migration of kinocilia are critical indicators of planar cell polarity （PCP） of hair cells. LKB1 deficiency in LKB1Pax2 CKO mice thus disrupted hair cell planar polarity during embryonic development. Our results suggest that LKB1 is required in PCP formation in cochlear hair cells in mice.

关键词： LKB1 stereociliary bundles kinocilium planar cell polarity hearing mice