Protein Isoforms; Receptor, trkC; Srsf1 protein, mouse; Elavl1 protein, mouse; Animals; Alternative Splicing; Mammals/metabolism; Neurons/metabolism; Protein Isoforms/genetics; Protein Isoforms/metabolism; Mice; Cell Line, Tumor; Neocortex/metabolism; Receptor, trkC/chemistry; Receptor, trkC/genetics; Receptor, trkC/metabolism; Mammals; Neocortex; Neurons; Genetics
Abstract :
[en] The seat of higher-order cognitive abilities in mammals, the neocortex, is a complex structure, organized in several layers. The different subtypes of principal neurons are distributed in precise ratios and at specific positions in these layers and are generated by the same neural progenitor cells (NPCs), steered by a spatially and temporally specified combination of molecular cues that are incompletely understood. Recently, we discovered that an alternatively spliced isoform of the TrkC receptor lacking the kinase domain, TrkC-T1, is a determinant of the corticofugal projection neuron (CFuPN) fate. Here, we show that the finely tuned balance between TrkC-T1 and the better known, kinase domain-containing isoform, TrkC-TK+, is cell type-specific in the developing cortex and established through the antagonistic actions of two RNA-binding proteins, Srsf1 and Elavl1. Moreover, our data show that Srsf1 promotes the CFuPN fate and Elavl1 promotes the callosal projection neuron (CPN) fate in vivo via regulating the distinct ratios of TrkC-T1 to TrkC-TK+. Taken together, we connect spatio-temporal expression of Srsf1 and Elavl1 in the developing neocortex with the regulation of TrkC alternative splicing and transcript stability and neuronal fate choice, thus adding to the mechanistic and functional understanding of alternative splicing in vivo.
Disciplines :
Neurology
Author, co-author :
Weber, A Ioana ; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany ; Freie Universität Berlin, Institute of Chemistry and Biochemistry, Takustr. 6, 14195, Berlin, Germany
Parthasarathy, Srinivas; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany
Borisova, Ekaterina; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany ; Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009, Tomsk, Russia
Epifanova, Ekaterina ; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany
Preußner, Marco; Freie Universität Berlin, Institute of Chemistry and Biochemistry, Takustr. 6, 14195, Berlin, Germany
Rusanova, Alexandra; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany ; Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009, Tomsk, Russia
Ambrozkiewicz, Mateusz C; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany
Bessa, Paraskevi ; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany
Newman, Andrew G ; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany
Müller, Lisa; Heinrich Heine Universität Düsseldorf, Institute of Virology, Medical Faculty, Universitätsstr. 1, 40225 Düsseldorf, Germany
Schaal, Heiner; Heinrich Heine Universität Düsseldorf, Institute of Virology, Medical Faculty, Universitätsstr. 1, 40225 Düsseldorf, Germany
Heyd, Florian ; Freie Universität Berlin, Institute of Chemistry and Biochemistry, Takustr. 6, 14195, Berlin, Germany
Tarabykin, Victor; Charité Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany ; Institute of Neuroscience, Lobachevsky State University of Nizhny Novgorod, 603950, Nizhny Novgorod Oblast, Russia
DFG - Deutsche Forschungsgemeinschaft [DE] RSF - Russian Science Foundation [RU] Boehringer Ingelheim [DE] Charité - Universitätsmedizin Berlin [DE]
Funding text :
V.T. was supported by the DFG [TA 303/11-1]; In utero electroporation experiments were funded by the 10th Russian Science Foundation (RSF) [22-14-00232]; I.W. was funded by the PhD fellowship of the Boehringer Ingelheim Fonds and a stipend from Charité Universitätsmedizin Berlin. Funding for open access charge: Lab funding.
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