Die Rolle des Id3 Proteins als transkriptioneller Regulator der neuronalen Differenzierung in ZNS Verletzungen oder Krankheiten
Zusammenfassung der Projektergebnisse
The adult central nervous system (CNS) was considered a comparatively static tissue with little cell turnover. It is now well established that there is more plasticity than previously thought and that astrocytes in specific areas of the CNS, namely the subventricular zone (SVZ) act as stem cells for the generation of neuronal cells. The discovery that these neural stem / precursor cells (NSPCs) can give rise to a limited number of new neurons, reactive astrocytes and oligodendrocytes contributing to brain repair in CNS disease, has raised hopes toward harnessing these cells for therapeutic interventions. Here, we aimed to further understand the molecular mechanisms regulating the generation of neuronal cells and astrocytes from these NSPCs. We found that the balance of the transcription factor E47 and its negative regulator Id3 controls the generation of astrocytes from NSPCs. In more detail, we found that genetic depletion of Id3 decreased the number of astrocytes generated from SVZ-derived adult NSPCs in the cortical lesion area after traumatic brain injury. Cortical brain injury resulted in rapid BMP-2 and Id3 up-regulation in the SVZ stem cell niche. Id3-deficient adult NSPCs failed to differentiate into BMP-2-induced astrocytes, while NSPCs deficient for the Id3-controlled transcription factor E47 readily differentiated into astrocytes in the absence of BMP-2 in vitro. Mechanistically, E47 repressed the expression of several astrocytespecific genes in adult NSPCs. These results identify Id3 as the BMP-2-induced transcriptional regulator, promoting adult NSPC differentiation into astrocytes upon CNS injury and reveal a molecular link between environmental changes and NSPC differentiation in the CNS after injury. We believe that understanding the in vivo differentiation potential and the molecular underpinnings of NSPCs in the adult mammalian brain will help us to evaluate their contributions to brain repair and may lead to new concepts in treating human CNS disease.
Projektbezogene Publikationen (Auswahl)
-
2012. Vascular damage in the central nervous system: a multifaceted role for vascular-derived TGF-β. Cell Tissue Res 347:187-201
Beck K, Schachtrup C
-
2013. Isolation and Culture of Mouse Cortical Astrocytes. J Vis Exp 71:e50079
Schildge S, Bohrer C, Beck K, Schachtrup C
-
2014. Instructions from the Vasculature - Directing Neural Stem Cell Fate in Health and Disease. Curr Med Chem 21:2190-2207
Schildge S, Bohrer C, Pfurr S, Mammadzada K, Schachtrup K, Schachtrup C
-
2015. Id3 Controls Fasmediated Deletion of 2B4+ Virus-specific CD8+ T Cells in Chronic Viral Infection. J Immunol
Menner AJ, Aichele P, Pircher H, Schachtrup C, Schachtrup K
-
2015. Nuclear pore complex remodeling by the cleaved p75 neurotrophin receptor regulates TGF-beta signaling and astrocyte scar formation. Nat Neurosci, 18:1077-80
Schachtrup C, Ryu JK, Mammadzada K, Khan AS, Carlton PM, Perez A, Christian F, Le Moan N, Perez A, Vagena E, Baeza-Raja B, Rafalski V, Chan JP, Nitschke R, Houslay MD, Ellisman MH, Wyss-Coray T, Palop JJ, Akassoglou K
-
2015. The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes. EMBO J, 34:2804-19
Bohrer C, Pfurr S, Mammadzada K, Schildge S, Plappert L, Hils M, Pous L, Rauch K, Dumit V, Pfeifer D, Dengjel J, Kirsch M, Schachtrup K, Schachtrup C
-
2016. ID(ealizing) control of adult subventricular zone neural stem/precursor cell differentiation for CNS regeneration. Neurogenesis, 3:e1223532. eCollection
Bohrer C, Schachtrup C.
-
2016. Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3. Cell Rep, 17:2827-2836
Rauch KS, Hils M, Lupar E, Minguet S, Sigvardsson M, Rottenberg ME, Izcue A, Schachtrup C, Schachtrup K
