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

Abstract

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.

PBX‐WNT‐P63‐IRF6 pathway in nonsyndromic cleft lip and palate

“…This suggests that this variant might contribute to lower PBX1 expression, corroborating the findings in the mouse model (Ferretti et al, ). Lastly, TP63 rs9332461 alternate allele G was predicted to have preferential binding to NKX2‐1, a transcription factor in brain, lung, and thyroid development (Manoli & Driever, ; Minocha et al, ). It was also located in enhancer mark‐rich regions in bone and muscle tissues.…”

Is Benign Hereditary Chorea Really Benign? Brain‐Lung‐Thyroid Syndrome Caused by NKX2‐1 Mutations

“…The transcription factor also may be involved in the generation of telencephalic astrocytes . Recent work in rodent models suggests that it may be important for the development of spatial learning and memory …”

“…25 Recent work in rodent models suggests that it may be important for the development of spatial learning and memory. 26 The NKX2-1 gene is expressed in the lung bud and thyroid primordium during embryogenesis and continues to be expressed in adult human lung and thyroid. 17 In thyroid tissue, NKX2-1 is instrumental in the formation of the thyroid bud and is important in the functional differentiation of the gland in late development and postnatally.…”

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

“…Based on in vitro studies, CD44 has long been considered a marker of astrocyte-restricted precursors (ARP) (Liu et al 2004); however, recent in vivo studies with more advanced lineage-tracing methodology revealed that CD44(+) cells can also yield OPCs (Naruse et al 2013). The latest studies revealed that the Nkx2.1 transcription factor determines astrocytic fate, but only in the dorsal telencephalon (Minocha et al 2017). In addition, in vitro conditions can deregulate the fate of progenitor cells, and thus some caution is warranted with the current view of downstream cell differentiation (Dromard et al 2007).…”

“…(1) cells can also yield OPCs (Naruse, Shibasaki, Yokoyama, Kurachi, & Ishizaki, 2013). The latest studies revealed that the Nkx2.1 transcription factor determines astrocytic fate, but only in the dorsal telencephalon (Minocha et al, 2017). In addition, in vitro conditions can deregulate the fate of progenitor cells, and thus some caution is warranted with the current view of downstream cell differentiation (Dromard et al, 2007).…”