CD93 negatively regulates astrogenesis in response to MMRN2 through transcription repressor ZFP503 in the developing brain

Astrogenesis is repressed in the early embryonic period, and occurs in the late embryonic period. A variety of external and internal signals contribute to the sequential differentiation of neural stem cell. Here, we discover that the immune-related CD93 plays a critical role in the onset of astrogenesis in mouse. CD93 expression is detected in neural stem cell and neuron but bot in astrocyte, and declines as differentiation proceeds. CD93 knockout increases astrogenesis at the expense of neuron production during the late embryonic period. CD93 responds to the ECM protein MMRN2 to trigger the repression of astrogenesis. In mechanism, CD93 delivers the signal through a series of phosphorylation cascade to β-Catenin, then β-Catenin transfers to nucleus to activate Zfp503 transcription. The transcription repressor ZFP503 inhibits Gfap transcription by binding to the Gfap promoter with the help of Grg5. Furthermore, the abnormal differentiation in astrogenesis and neurogenesis caused by CD93 knockout results in autism-like behaviors. Taken together, our study reveals that CD93 is a negative regulator in controlling the proper time of astrogenesis, and provides a new sight in therapy for psychiatric disorders.