title: The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation.
abstract: Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development. The present study reports a hypoparathyroidism-associated mutation R59L that alters Drosophila Gcm (Gcm) protein stability, rendering it unstable, and hyperubiquitinated via the ubiquitin-proteasome system (UPS). GcmR59Linteracts with the Slimb-based SCF complex and Protein Kinase C (PKC), which possibly plays a role in its phosphorylation, hence altering ubiquitination. Additionally, R59L causes reduced Gcm protein levels in a manner independent of the PEST domain signaling protein turnover. GcmR59Lproteins bind DNA, functionally activate transcription, and induce glial cells, yet at a less efficient level. Finally, overexpression of either wild-type human Gcmb (hGcmb) or hGcmb carrying the conserved hypoparathyroidism mutation only slightly affects gliogenesis, indicating differential regulatory mechanisms in human and flies. Taken together, these findings demonstrate the significance of this disease-associated mutation in controlling Gcm protein stability via UPS, hence advance our understanding on how glial formation is regulated.
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xi
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Chun-Chun
authors.initials: CC
authors.lastname: Zhuge
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Yuanfen
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Haian
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Biomedical Sciences and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Chang-Ching
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Biomedical Sciences and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Bertrand Chin-Ming
authors.initials: BC
authors.lastname: Tan
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Lee
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Cheng-Ting
authors.initials: CT
authors.lastname: Chien
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.|Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Ho
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007011:Hypoparathyroidism / Q000378:metabolism / Q000473:pathology*; D007976:Leupeptins / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D055550:Protein Stability; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C102805:GCM protein, Drosophila; C119532:GCM2 protein, human; D007976:Leupeptins; D009687:Nuclear Proteins; D014157:Transcription Factors; D025801:Ubiquitin; D004247:DNA; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde