Ventral Neural Stem Cells Research Articles

Relative Levels of Gli1 and Gli2 Determine the Response of Ventral Neural Stem Cells to Demyelination.

SummaryEnhancing repair of myelin is an important therapeutic goal in many neurological disorders characterized by demyelination. In the healthy adult brain, ventral neural stem cells (vNSCs) in the subventricular zone, marked by GLI1 expression, do not generate oligodendrocytes. However, in response to demyelination, their progeny are recruited to lesions where they differentiate into oligodendrocytes and ablation of GLI1 further enhances remyelination. GLI1 and GLI2 are closely related transcriptional activators but the role of GLI2 in remyelination by vNSCs is not clear. Here, we show that genetic ablation of Gli1 in vNSCs increases GLI2 expression and combined loss of both transcription factors decreases the recruitment and differentiation of their progeny in demyelinated lesions. These results indicate that GLI1 and GLI2 have distinct, non-redundant functions in vNSCs and their relative levels play an essential role in the response to demyelination.

Nkx2.1 regulates the generation of telencephalic astrocytes during embryonic development

The homeodomain transcription factor Nkx2.1 (NK2 homeobox 1) controls cell differentiation of telencephalic GABAergic interneurons and oligodendrocytes. Here we show that Nkx2.1 also regulates astrogliogenesis of the telencephalon from embryonic day (E) 14.5 to E16.5. Moreover we identify the different mechanisms by which Nkx2.1 controls the telencephalic astrogliogenesis. In Nkx2.1 knockout (Nkx2.1−/−) mice a drastic loss of astrocytes is observed that is not related to cell death. Further, in vivo analysis using BrdU incorporation reveals that Nkx2.1 affects the proliferation of the ventral neural stem cells that generate early astrocytes. Also, in vitro neurosphere assays showed reduced generation of astroglia upon loss of Nkx2.1, which could be due to decreased precursor proliferation and possibly defects in glial specification/differentiation. Chromatin immunoprecipitation analysis and in vitro co-transfection studies with an Nkx2.1-expressing plasmid indicate that Nkx2.1 binds to the promoter of glial fibrillary acidic protein (GFAP), primarily expressed in astrocytes, to regulate its expression. Hence, Nkx2.1 controls astroglial production spatiotemporally in embryos by regulating proliferation of the contributing Nkx2.1-positive precursors.

Transplantation of GABAergic neurons into adult mouse neocortex

GABAergic neurons in the neocortex contribute to various brain functions by regulating cortical pyramidal neurons. A deficiency of GABAergic neurons in the neocortex leads to the dysregulation of cortical neuronal circuits, but this can be overcome by cell transplantation, which provides a practical approach to repair damaged neuronal circuits. Here, we focused on the transplantation of committed neuronal progenitor cells. Because neuronal differentiation is considerably suppressed in the adult neocortex, we transfected proneural bHLH transcription factors into neural precursor cells to commit them to a neuronal lineage prior to the cell transplantation. We show that ventral neural stem cells transfected with Ngn1 are integrated as GABAergic neurons within a few days of transplantation into the adult mouse neocortex. These results demonstrate that the transplantation of committed neuronal progenitor cells is an effective method for brain repair.