Astrogenesis
In the developing neural system, the three major cell types namely neurons, astrocytes and oligodendrocytes share common ancestors, neural stem cells or progenitor cells. In the initial phase of neural development, neural stem cells contribute to neurogenesis followed by a wave of gliogenesis. Two of the major signaling pathways known to contribute to activation of astrogenesis are the JAK/STAT and Notch. Upstream extrinsic factors lead to the activation of these pathways. The major players are IL-6 cytokine family members, CNTF, LIF and CT-1, which along with BMP and Notch signaling lead to stimulation of astrogenesis.
One major impact of these factors is STAT3 activation. STAT3 is essential in the induction of expression of astrocyte-lineage specific genes including GFAP and S100B at the transcriptional level. STAT3 is a core component of the STAT3:p300/CBP:SMAD1 transcriptional complex modulating activation of factors involved in astrogenesis. Other transcription factors involved in the process include SOX9 and HES1. Furthermore, chromatin modifications such as demethylation of the GFAP promoter must occur for astrocyte development to proceed.
Astrocytes in human neurodevelopmental disorders
It is becoming increasingly apparent that astrocytes are highly significant when there is disruption of the choreography of neural development, leading to disease pathogenesis in neurodevelopmental disorders.
Lessons from monogenetic forms of autism have shown that primary astrocyte dysfunction can underlie these disorders. For example, Rett syndrome, caused by mutations in methyl CpG binding protein 2 (MECP2), features abnormal dendritic morphology and altered synapse physiology. Patients with schizophrenia express increased levels of glial fibrillary acidic protein (GFAP), which is a feature associated with astrogliosis.
Understanding the impact of astrocyte dysfunction and behavior, including the impact on surrounding neurons, is of high importance in understanding the underlying causes of such disorders and will pave the way towards future therapies.
Astrocytes and neurodegeneration
Neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases have long been studied from the viewpoint of degeneration of neuronal populations. Evidence suggests that glial atrophy often appears at early disease stages, for example, in amyotrophic lateral sclerosis (ALS), degeneration of astrocytes occurs prior to symptoms caused by motor-neuron defects. Moreover, activation of astrocytes has been linked to production of amyloid beta in Alzheimer’s disease therefore providing a contribution to amyloid plaque formation.
