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Multiple routes to astrocytic differentiation in the CNS
1Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4157, USA.
Abstract:
Ciliary neurotrophic factor (CNTF) acts instructively to switch multipotent stem cells of the CNS to an astrocytic fate. Here we show that CNTF causes activation of janus kinase-signal transducers and activators of transcription and mitogen-activated protein kinase (MAPK) pathways with differential kinetics in these cells. Inhibition studies indicate that activation of the MAPK pathway is required early in the differentiation process, whereas activation of signal transducer and activator of transcription (STAT) proteins is required for commitment to an astrocytic fate. Bone morphogenetic proteins have also been shown to cause astrocytic differentiation but do not cause STAT activation or astrocytic differentiation in fibroblast growth factor 2-expanded fetal stem cells used here. These results show that there are two distinct routes to initiate astrocytic commitment in multipotent CNS precursors.
Insights
Ciliary neurotrophic factor (CNTF) directs central nervous system (CNS) stem cells to become astrocytes. This involves distinct janus kinase-STAT and MAPK pathway activations, with MAPK needed early and STAT for commitment.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Signaling
Background:
- Multipotent stem cells in the CNS can differentiate into various cell types, including astrocytes.
- Ciliary neurotrophic factor (CNTF) is known to induce astrocytic differentiation.
Purpose of the Study:
- To elucidate the specific signaling pathways involved in CNTF-induced astrocytic differentiation.
- To compare CNTF-induced differentiation with other known astrocytic differentiation inducers like bone morphogenetic proteins.
Main Methods:
- Investigated the activation kinetics of janus kinase-signal transducers and activators of transcription (STAT) and mitogen-activated protein kinase (MAPK) pathways.
- Utilized inhibition studies to determine the necessity of each pathway during differentiation.
- Examined astrocytic differentiation in fetal stem cells expanded with fibroblast growth factor 2.
Main Results:
- CNTF activates both STAT and MAPK pathways with distinct temporal profiles.
- MAPK pathway activation is required early in the differentiation process.
- STAT protein activation is essential for the final commitment to an astrocytic fate.
- Bone morphogenetic proteins induce astrocytic differentiation but do not activate STAT pathways in the studied stem cells.
Conclusions:
- Two distinct signaling routes can initiate astrocytic commitment in multipotent CNS precursors.
- CNTF utilizes a pathway involving early MAPK activation followed by STAT activation for astrocytic differentiation.
- This contrasts with other inducers like bone morphogenetic proteins, highlighting pathway specificity in CNS development.