title: Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment.
abstract: To study nucleolar involvement in brain development, the nuclear and nucleolar proteomes from the rat cerebral cortex at postnatal day 7 were analyzed using LC-MS/iTRAQ methodology. Data of the analysis are available via ProteomeXchange with identifier PXD002188. Among 504 candidate nucleolar proteins, the overrepresented gene ontology terms included such cellular compartmentcategories as "nucleolus", "ribosome" and "chromatin". Consistent with such classification, the most overrepresented functional gene ontology terms were related to RNA metabolism/ribosomal biogenesis, translation, and chromatin organization. Sixteen putative nucleolar proteins were associated with neurodevelopmental phenotypes in humans. Microcephaly and/or cognitive impairment were the most common phenotypic manifestations. Although several such proteins have links to ribosomal biogenesis and/or genomic stability/chromatin structure (e.g. EMG1, RPL10, DKC1, EIF4A3, FLNA, SMC1, ATRX, MCM4, NSD1, LMNA, or CUL4B), others including ADAR, LARP7, GTF2I, or TCF4 have no such connections known. Although neither the Alazami syndrome-associated LARP7nor the Pitt-Hopkins syndrome-associated TCF4 were reported in nucleoli of non-neural cells, in neurons, their nucleolar localization was confirmed by immunostaining. In cultured rat hippocampal neurons, knockdown of LARP7 reduced both perikaryal ribosome content and general protein synthesis. Similar anti-ribosomal/anti-translation effects were observed after knockdown of the ribosomal biogenesis factor EMG1 whose deficiency underlies Bowen-Conradi syndrome. Finally, moderate reduction of ribosome content and general protein synthesis followed overexpression of two Pitt-Hopkins syndrome mutant variants of TCF4. Therefore, dysregulation of ribosomal biogenesis and/or other functions of the nucleolus may disrupt neurodevelopment resulting in such phenotypes as microcephaly and/or cognitive impairment.
authors.affiliation: From the ‡Kentucky Spinal Cord Injury Research Center and the Departments of Neurological Surgery and.
authors.forename: Lukasz P
authors.initials: LP
authors.lastname: Slomnicki
authors.affiliation: ¶Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland;
authors.forename: Agata
authors.initials: A
authors.lastname: Malinowska
authors.affiliation: ¶Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland;
authors.forename: Michal
authors.initials: M
authors.lastname: Kistowski
authors.affiliation: ‖Department of Systems Biology, Faculty of Biology, University of Warsaw, Warsaw, Poland;
authors.forename: Antoni
authors.initials: A
authors.lastname: Palusinski
authors.affiliation: From the ‡Kentucky Spinal Cord Injury Research Center and the Departments of Neurological Surgery and.
authors.forename: Jing-Juan
authors.initials: JJ
authors.lastname: Zheng
authors.affiliation: **Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
authors.forename: Mari
authors.initials: M
authors.lastname: Sepp
authors.affiliation: **Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
authors.forename: Tonis
authors.initials: T
authors.lastname: Timmusk
authors.affiliation: ¶Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland;
authors.forename: Michal
authors.initials: M
authors.lastname: Dadlez
authors.affiliation: From the ‡Kentucky Spinal Cord Injury Research Center and the Departments of Neurological Surgery and §Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; michal.hetman@louisville.edu.
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002466:Cell Nucleolus / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism; D005260:Female; D006801:Humans; D023421:Models, Animal; D009687:Nuclear Proteins / Q000302:isolation & purification*; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012270:Ribosomes / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins