Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator 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 À/À 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. Mechanistically, E47 repressed the expression of several astrocyte-specific 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.

Astrocytes play critical roles in neuronal activity and inhibition of regeneration. Here we show that the cleaved p75 neurotrophin receptor (p75NTR) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of TGF-β signaling. The cleaved p75NTR interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75NTR controls astrocyte-neuronal communication in response to profibrotic factors.

During corticogenesis, distinct classes of neurons are born from progenitor cells located in the ventricular and subventricular zones, from where they migrate towards the pial surface to assemble into highly organized layer-specific circuits. However, the precise and coordinated transcriptional network activity defining neuronal identity is still not understood. Here, we show that genetic depletion of the basic helix-loop-helix (bHLH) transcription factor E2A splice variant E47 increased the number of Tbr1-positive deep layer and Satb2-positive upper layer neurons at E14.5, while depletion of the alternatively spliced E12 variant did not affect layer-specific neurogenesis. While ChIP-Seq identified a big overlap for E12- and E47-specific binding sites in embryonic NSCs, including sites at the cyclin-dependent kinase inhibitor (CDKI) gene locus, RNA-Seq revealed a unique transcriptional regulation by each splice variant. E47 activated the expression of the CDKI through binding to a distal enhancer. Finally, overexpression of E47 in embryonic NSCs impaired neurite outgrowth, and overexpression of E47 by electroporation disturbed proper layer-specific neurogenesis and upregulated p57(KIP2) expression. Overall, this study identifies E2A target genes in embryonic NSCs and demonstrates that E47 regulates neuronal differentiation via p57(KIP2).

The vascular system distributes oxygen and nutrients to all tissues in the body. Additionally, the vascular system also functions in hosting and instructing tissue-specific stem and progenitor cells. Both cell- or blood-derived signals from the vascular system regulate stem cell properties in health and disease. Studies in animal models and in human disease have begun to uncover that signals from the vascular system are not merely maintaining the stem cell niche, but also instruct stem cells for repair mechanisms outside their niche. The present article focuses on recent findings about cell- or blood-derived factors in the vascular system supporting stem cell niche maintenance or activation for tissue homeostasis and repair. We highlight the fact that certain aspects of vascular - stem cell communication are conserved between stem cell niches in different tissues. Within this context, we will especially emphasize on a potential role of the altered vascular system after CNS disease in instructing stem cell fate. Understanding the communication between the vascular system and neural stem cells might support the development for new therapeutic approaches for CNS disease.