Universität zu Köln

Koch, Peter, Loehr, Heiko B. and Driever, Wolfgang ORCID: 0000-0002-9551-9141 (2014). A Mutation in cnot8, Component of the Ccr4-Not Complex Regulating Transcript Stability, Affects Expression Levels of Developmental Regulators and Reveals a Role of Fgf3 in Development of Caudal Hypothalamic Dopaminergic Neurons. PLoS One, 9 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

While regulation of the activity of developmental control genes at the transcriptional level as well as by specific miRNA-based degradation are intensively studied, little is known whether general cellular mechanisms controlling mRNA decay may contribute to differential stability of mRNAs of developmental control genes. Here, we investigate whether a mutation in the deadenylation dependent mRNA decay pathway may reveal differential effects on developmental mechanisms, using dopaminergic differentiation in the zebrafish brain as model system. In a zebrafish genetic screen aimed at identifying genes controlling dopaminergic neuron development we isolated the m1061 mutation that selectively caused increased dopaminergic differentiation in the caudal hypothalamus, while other dopaminergic groups were not affected. Positional cloning revealed that m1061 causes a premature stop codon in the cnot8 open reading frame. Cnot8 is a component of the Ccr4-Not complex and displays deadenylase activity, which is required for removal of the poly (A) tail in bulk mRNA turnover. Analyses of expression of developmental regulators indicate that loss of Cnot8 activity results in increased mRNA in situ hybridization signal levels for a subset of developmental control genes. We show that in the area of caudal hypothalamic dopaminergic differentiation, mRNA levels for several components of the FGF signaling pathway, including Fgf3, FGF receptors, and FGF target genes, are increased. Pharmacological inhibition of FGF signaling or a mutation in the fgf3 gene can compensate the gain of caudal hypothalamic dopaminergic neurons in cnot8(m1061) mutants, indicating a role for Fgf3 in control of development of this dopaminergic population. The cnot8m1061 mutant phenotype provides an in vivo system to study roles of the Cnot8 deadenylase component of the mRNA decay pathway in vertebrate development. Our data indicate that attenuation of Cnot8 activity differentially affects mRNA levels of developmental control genes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Koch, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Loehr, Heiko B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Driever, Wolfgang UNSPECIFIED orcid.org/0000-0002-9551-9141 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-420897
DOI:	10.1371/journal.pone.0113829
Journal or Publication Title:	PLoS One
Volume:	9
Number:	12
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MESSENGER-RNA DECAY; DEVELOPING ZEBRAFISH BRAIN; ISOTOCIN CELL-DEVELOPMENT; SACCHAROMYCES-CEREVISIAE; CATECHOLAMINERGIC SYSTEM; MONOAMINERGIC NEURONS; HOMEODOMAIN PROTEIN; DEADENYLASE COMPLEX; GENETIC-ANALYSIS; CAF1 PROTEINS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42089