Deshpande, Sachin S.
[Author]
;
Schachtrup, Christian
[Degree supervisor]Albert-Ludwigs-Universität Freiburg Institut für Anatomie und Zellbiologie,
Albert-Ludwigs-Universität Freiburg Fakultät für Biologie
The role of the p75 neurotrophin receptor (p75NTR) in adult neural stem/precursor cell properties after cortical injury
University thesis:
Dissertation, Universität Freiburg, 2020
Footnote:
Description:
Abstract: CNS injuries create an inhibitory niche for active regeneration. The factors involved in this phenomenon have established a perplexing paradigm for researchers hoping to develop an effective therapeutic measure towards recovery. An attempt to advance the use of therapeutic procedures have led to investigation of neural stem / progenitor cells (NSPCs) as a powerful tool to redeem the loss of cellular integrity in CNS. Understanding the underlying molecular mechanism in NSPCs is crucial for favorable utilization of these cells in pathologic conditions. The lack of sufficient knowledge about factors fundamental to the functioning of NSPCs during debilitating CNS injuries motivated us to undertake this project in order to uncover the basic mechanisms of NSPC function in physiological and pathological functions. The p75NTR (Neurotrophin receptor) is classically known to be a factor influencing survival and apoptosis of neurons in CNS injury and disease based of context such as ligand and co-receptor interaction. It is also involved in activating astrocytes under the influence of fibrotic conditions such as TGF-β. Such contrasting features of p75NTR expression and function based on the cell type in the CNS led us to investigate its potential to regulate NSPC functionalities, which are capable to generate neurons and astrocytes. Previous studies from our lab have demonstrated an altered microenvironment in SVZ after cortical injury, showing an increased deposition of BMP and fibrinogen around the NSPCs. Here we show that the p75NTR is rapidly upregulated in NSPCs in an altered microenvironment due to blood derived factors after cortical ischemia. Additionally, we demonstrate p75NTR to be required for optimum response of NSPC migration from SVZ towards the lesion area. Neurogenic markers such as PSA-NCAM and Tuj1 are downregulated in p75NTR knockout mice, without affecting the overall neuroblast population. Our in-vitro assays revealed p75NTR cleavage by secretases to be mechanistically involved in neuronal differentiation. P75NTR is observed to be required for efficient SMAD1 shuttling post BMP-2 treatment in NSPCs. This effect is likely correlated with mis-regulation of FG- Nucleoporins in p75NTR-/- NSPCs. It regulates cytoskeletal organization related genes in proliferating NSPCs. P75NTR is also implicated to modulate BDNF deposition in SVZ after injury. Surprisingly, over expression of p75NTR in NSPCs generates highly ramified neurons displaying markers of functional integration like GAP-43 and synaptophysin. This study provides ample evidence to show the multi-faceted role of p75NTR in regulating NSPC function in context of CNS injuries