Sox2 regulates astrocytic and vascular development in the retina

Abstract

Sox2 is a transcriptional regulator that is highly expressed in retinal astrocytes, yet its function in these cells has not previously been examined. To understand its role, we conditionally deleted Sox2 from the population of astrocytes and examined the consequences on retinal development. We found that Sox2 deletion does not alter the migration of astrocytes, but it impairs their maturation, evidenced by the delayed upregulation of glial fibrillary acidic protein (GFAP) across the retina. The centro-peripheral gradient of angiogenesis is also delayed in Sox2-CKO retinas. In the mature retina, we observed lasting abnormalities in the astrocytic population evidenced by the sporadic loss of GFAP immunoreactivity in the peripheral retina as well as by the aberrant extension of processes into the inner retina. Blood vessels in the adult retina are also under-developed and show a decrease in the frequency of branch points and in total vessel length. The developmental relationship between maturing astrocytes and angiogenesis suggests a causal relationship between the astrocytic loss of Sox2 and the vascular architecture in maturity. We suggest that the delay in astrocytic maturation and vascular invasion may render the retina hypoxic, thereby causing the abnormalities we observe in adulthood. These studies uncover a novel role for Sox2 in the development of retinal astrocytes and indicate that its removal can lead to lasting changes to retinal homeostasis.

Retinal blood vessel‐origin yes‐associated protein (YAP) governs astrocytic maturation via leukaemia inhibitory factor (LIF)

“…Astrocyte maturation is regulated by classic regulators, such as SOX2, which is a highly conserved transcriptional factor in all stages of central nervous system development. 42 Dentin matrix protein 1-proteoglycan (DMP1-PG) 43 and astrocytic contact 44 are also required for astrocyte maturation.…”

Large-scale death of retinal astrocytes during normal development mediated by microglia

“…However, if microglia mediate clearance but not death, ablation would be expected to increase the number of corpses without a similar increase in the number of differentiated astrocytes. To distinguish between these possibilities we stained microglia-ablated retinas for GFAP, a late marker of retinal astrocyte differentiation that also reveals cellular morphology [28,30,56]. Nearly all (>98.8%) Pax2 + or Sox9 + astrocytes co-expressed GFAP by P10, regardless of whether microglia had been ablated (Control: n=2,642 astrocytes; DTR: n=4,145 astrocytes; N=3 animals per condition).…”

The stem cell transcription factor SOX2 is essential for astrocyte maturation and controls animal hyperactive behavior

“…Previous study using Cag-CreER T2 :Sox2 fl/fl mice has reported that SOX2 deletion does not affect astrocyte development in the spinal cord (11). In contrast, SOX2 is recently reported to regulate astrocyte maturation in the retina of hGFAP-Cre:Sox2 fl/fl mice (17). However, hGFAP-Cre mediates gene disruption in embryonic multi-potential NSCs, NSC-derived glial/neuronal cells, and retinal Muller glia as indicated by reporter gene expression (18).…”

“…Astroglial-specific SOX2 deletion paradigms are necessary to study the role of SOX2 in astrocyte maturation in vivo. Furthermore, much of our current knowledge of SOX2 in astrocyte development is largely based on GFAP immunostaining (11,17), which displays intrinsic limitations for astrocyte visualization despite its importance in assessing astrocyte maturation. The direct delineation of the role of SOX2 in postnatal astrocyte development and animal behavior is still very limited, and how SOX2 regulates astrocyte maturation is largely unknown.…”