title: midlife crisis encodes a conserved zinc-finger protein required to maintain neuronal differentiation in Drosophila.
abstract: Stem cells generate progeny that undergo terminal differentiation. The initiation and maintenance of the differentiated status is crucial for tissue development, function and homeostasis. Drosophila neural stem cells (neuroblasts) are a model for stem cell self-renewal and differentiation; they divide asymmetrically to self-renew and generate the neurons and glia of the CNS. Here we report the identification of midlife crisis (mdlc; CG4973) as a gene required for the maintenance of neuronal differentiation and for neuroblast proliferation in Drosophila. mdlc encodes a ubiquitously expressed zinc-finger-containing protein with conserved orthologs from yeast to humans that are reported to have a role in RNA splicing. Using clonal analysis, we demonstrate that mdlc mutant neurons initiate but fail to complete differentiation, as judged by the loss of the pro-differentiation transcription factor Prospero, followed by derepression of the neuroblast factors Deadpan, Asense and Cyclin E. RNA-seq shows that loss of Mdlc decreases pros transcript levels and results in aberrant pros splicing. Importantly, misexpression of the full-length human ortholog, RNF113A, completely rescues all CNS defects in mdlc mutants. We conclude that Mdlc plays an essential role in maintaining neuronal differentiation, raising the possibility that RNF113A regulates neuronal differentiation in the human CNS.
authors.affiliation: Institute of Molecular Biology, Institute of Neuroscience, Howard Hughes Medical Institute, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Travis D
authors.initials: TD
authors.lastname: Carney
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Struck
authors.forename: Chris Q
authors.initials: CQ
authors.lastname: Doe
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D019927:Cyclin E / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D012326:RNA Splicing; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016335:Zinc Fingers
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C407353:ase protein, Drosophila; C584829:mdlc protein, Drosophila; C073099:pros protein, Drosophila; C078020:Dpn protein, Drosophila
keywords: Neuroblast; Neuron; Prospero; Self-renewal; Splicing; Stem cell
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