Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex

Abstract

In response to central nervous system (CNS) injury, astrocytes go through a series of alterations, referred to as reactive astrogliosis, ranging from changes in gene expression and cell hypertrophy to permanent astrocyte borders around stromal cell scars in CNS lesions. The mechanisms underlying injury-induced reactive astrocytes in the adult CNS have been extensively studied. However, little is known about injuryinduced reactive astrocytes during early postnatal development. Astrocytes in the mouse cortex are mainly produced through local proliferation during the first 2 weeks after birth. Here we show that Sox2, a transcription factor critical for stem cells and brain development, is expressed in the early postnatal astrocytes and its expression level was increased in reactive astrocytes after traumatic brain injury (TBI) at postnatal day (P) 7 in the cortex. Using a tamoxifen-induced hGFAP-CreERT2; Sox2 flox/flox ; Rosa-tdT mouse model, we found that specific knockout of Sox2 in astrocytes greatly inhibited the proliferation of reactive astrocytes, the formation of glia limitans borders and subsequently promoted the tissue recovery after postnatal TBI at P7 in the cortex. In addition, we found that injury-induced glia limitans borders were still formed at P2 in the wild-type mouse cortex, and knockout of Sox2 in astrocytes inhibited the reactivity of both astrocytes and microglia. Together, these findings provide evidence that Sox2 is essential for the reactivity of astrocytes in response to the cortical TBI during the early postnatal period and suggest that Sox2-dependent astrocyte reactivity is a potential target for therapeutic treatment after TBI.

Amyloid precursor protein induces reactive astrogliosis

“…To examine whether our findings apply to realistic pathological contexts, we preliminarily build upon previous work in animal models of brain trauma. 22,[64][65][66][67] These previous studies, however, did not show the interaction between APP and IFN in reactive astrocytes revealed by the present study. In the attempt to translate our cell culture findings into pathophysiologically relevant animal models, we explored and observed an association between APP and IFN levels in reactive astrocytes affected by TBI.…”

“…Conversely, depletion of APP abrogates LPS‐induced reactive astrogliosis and reduces expression of ISG products. To examine whether our findings apply to realistic pathological contexts, we preliminarily build upon previous work in animal models of brain trauma 22,64–67 . These previous studies, however, did not show the interaction between APP and IFN in reactive astrocytes revealed by the present study.…”

Simultaneous profiling of full-length RNA transcripts and chromatin accessibility within single cells of human retinal organoids

“…3e). Furthermore, this consistency was also observed for fatedetermining factors of retinal neurons, such as HES1 in neurogenic RPCs 20 , SOX2 21,22 in RPCs, ATOH7 [23][24][25] in retinal ganglion cells (RGCs), OTX2 [26][27][28] in the PR precursor. Importantly, the RNA expression and chromatin accessibility patterns of these genes were aligned with their activity in different cell types.…”

Amyloid precursor protein induces reactive astrogliosis

“…To examine whether our findings apply to realistic pathological contexts, we build upon previous work in animal models of brain trauma 22,[64][65][66][67] . These previous studies, however, did not show the interaction between APP and IFN in reactive astrocytes revealed by the present study.…”