Role of Non-catalytic form of TrkC receptor in cell fate specification of neocortical progenitors
Final Report Abstract
The goal of the project was to dissect the mechanisms that control development of the different neuronal cell types in the neocortex. Specifically, we aimed to identify molecular mechanisms that act downstream of TrkC-T1 receptor. In the course of the project we discovered that TrkC-T1 regulates the switch in NPC fate from deep to upper layer neuron production during neocortical development. Furthermore, we could show that TrkC-T1 exerts this control by interaction with the signalling adaptor protein ShcA. This prevents the phosphorylation of Shc and the downstream activation of the MAP kinase (Erk1/2) pathway. We thus showed that the generation of upper layer neurons by late progenitors is dependent on the downregulation of TrkC-T1 in late progenitor cells and the resulting activation of the ShcA/Erk1/2 pathway. On the other hand, we discovered that preferential generation of TrkC- T1 isoform instead of TrkC-TK isoform in early versus late cortical progenitor is regulated by opposite action of two alternative splicing regulators Srsf1 and Elavl1. We showed that Srsf1 shifts the ratio of the T1 and TK+ transcript variants in favor of T1 and by doing so determines choice between subcortical and cortico-cortical projection neuron fate in the developing cortex. Elavl1 in contrast, has the opposite effect on both T1 and TK+ transcript ratio and cell fate in the neocortex.
Publications
- 2020. Srsf10 and the minor spliceosome control tissue-specific and dynamic SR protein expression. Elife. 9
Meinke S, Goldammer G, Weber AI, Tarabykin V, Neumann A, Preussner M, Heyd F
(See online at https://doi.org/10.7554/elife.56075) - 2020. Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury. Cell Rep. 31:107834
Vivinetto AL, Kim ID, Goldberg DC, Fones L, Brown E, Tarabykin VS, Hill CE, Cho S, Cave JW
(See online at https://doi.org/10.1016/j.celrep.2020.107834) - 2021. TrkC-T1, the Non-Catalytic Isoform of TrkC, Governs Neocortical Progenitor Fate Specification by Inhibition of MAP Kinase Signaling. Cereb Cortex
Parthasarathy S, Srivatsa S, Weber AI, Graber N, Britanova OV, Borisova E, Bessa P, Ambrozkiewicz MC, Rosario M, Tarabykin V
(See online at https://doi.org/10.1093/cercor/bhab172) - Neuroscience. 2021 May 21;463:303-316
Sokpor G, Rosenbusch J, Kunwar AJ, Rickmann M, Tuoc T, Rizzoli SO, Tarabykin V, von Mollard GF, Krieglstein K, Staiger JF
(See online at https://doi.org/10.1016/j.neuroscience.2021.03.021)
