The critical role of astrogenesis and neurodevelopment in Fragile X Syndrome and Rett Syndrome
Astrocytes play an important role in the development of functional neural circuits in the brain. They are responsible for coordinating synapse formation and function, axon guidance, and ensuring neuronal survival. Normal astrogenesis begins during late gestation. Neural stem cells (NSCs) become primarily gliogenic and differentiate to become astrocyte precursors. Through local proliferation and functional maturation, the precursors develop into mature astrocytes, which can either be fibrous or protoplasmic. Astrogenesis is regulated by both cell intrinsic programs and cell extrinsic cues. Intrinsic chromatin changes, such as demethylation of astrocyte-specific genes, allows the NSCs to become responsive to astrocyte-inducing exogenous cues. These cues involve a collaboration of multiple pathways, namely the Notch pathway, the bone morphogenetic protein (BMP) signaling pathway, interleukin-6 (IL-6) signaling, and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway. Together, they allow for normal astrogenesis to occur. However, disruption to these pathways lead to abnormal astrocyte development and results in pathologies such as the Fragile X Syndrome (FXS) and Rett Syndrome (RS). Both neurodevelopmental disorders are a result of genetic mutations that causes either transcriptional silence or transcriptional activation at inappropriate stages during development. These genetic mutations result in depressed astrocyte function in FXS, and the overexcitement of astrocytes in RS. The current hypothesis under investigation is that altered gene transcription during neurodevelopment disrupts astrogenesis, and subsequently, the behavior and function of mature astrocytes in the brain. Future research should focus on understanding the timing of the transition from neurogenesis to astrogenesis and identifying astrocyte-specific markers that are critical to its function in neurodevelopment.