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Molecular Control of Pyramidal Neuron Fate Determination in the Developing Neocortex

dc.contributor.advisorTarabykin, Victor Prof. Dr.
dc.contributor.authorParthasarathy, Srinivas
dc.titleMolecular Control of Pyramidal Neuron Fate Determination in the Developing Neocortexde
dc.contributor.refereeStegmüller, Judith Dr.
dc.description.abstractengThe pyramidal neurons of the neocortex, which form the neural substrate for our higher cognitive abilities, arise from a single layer of neuroepithelium lining the dorsal ventricles. It has been of immense interest to study how cell fate specification within the developing cortex dictates the generation of these numerous classes of pyramidal neurons from a small pool of cortical progenitors.  Others and we had previously shown that postmitotic neurons signal back to their progenitors and instruct the timing of cell fate switch. This process governs both the switch from producing one neuronal type to the other and from neurogenesis to gliogenesis. We have previously shown that Fgf9 controls the switch from neurogenesis to gliogenesis. While a similar mechanism governing the switch from deep layer to upper layer neuronal production was predicted, the precise molecular pathway was not shown.  In this thesis, we show that the neurotrophin Ntf3, signals back to cortical progenitors and initiates the shift from deep to upper layer cell fate. It does so by shifting the ratio of apical progenitors to basal progenitors, which in turn govern the production of cortical neurons. We go on to show that the effect of Ntf3 is most likely mediated by the truncated- Non Catalytic isoform of TrkC- NC-TrkC. NC-TrkC, to our knowledge, is the first molecule to show an expression pattern that parallels the timing of deep layer neurogenesis. Through gain-of-function experiments, we show that NC-TrkC expression tilts neurogenesis in favor of deeper layer neurons. We also show that the effect of NC-TrkC is most likely through the negative regulation of ERK signaling. We provide further evidence that signaling via the binding site for the signaling molecule Shc, on NC-TrkC is important for its role in cell fate determination. Further, we show a novel interaction between NC-TrkC and the BMP class I receptor BMPRIA. These receptors interact in vitro and in vivo. The genetic programs controlled by them interact to govern neuronal fate during corticogenesis.  Finally, we study the role of a family of transneuronal cytokines-Cbln, as molecules that function in parallel to Ntf3 in controlling neuronal fate switch in the cortex. We show that over-expression of the Cbln family members can also alter the proportions of apical and basal progenitors, thereby providing insights into new modes of signaling between postmitotic neurons and their progenitors. de
dc.contributor.coRefereeMarquardt, Till Prof. Dr.
dc.subject.engCortical developmentde
dc.subject.engCell fate specificationde
dc.subject.engFeedback signalingde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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