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Notch1 and Numb genes are inversely expressed as oligodendrocytes differentiate
Maria I Givogri1, Vilma Schonmann, Ruth Cole
1Laboratory for Gene Therapy of Neurodegenerative Disorders, San Raffaele Telethon Institute for Gene Therapy, Milano, Italy.
Abstract:
The Notch1 pathway plays a fundamental role during the establishment of cell fates in the central nervous system (CNS) by regulating neural cell differentiation. In oligodendrocytes (OLs), Notch1 activity prevents these cells from becoming terminally mature, thereby influencing CNS myelination. Little is known of how OLs regulate the expression of this receptor at the gene level or if OLs have mechanisms to control the level of intracellular activity of the Notch1 pathway. In this study, we have found that Notch1 gene expression was higher in proliferative OL progenitor cells (OPCs) and was reduced when cells were forced to withdraw from the cell cycle and became mature, indicating that Notch1 gene expression is developmentally regulated in OLs. We observed that the blockade of terminal differentiation of OPCs by incubation with Delta1, an activator of Notch1, was a dominant process and OL-differentiating signals such as thyroid hormone could not overcome this inhibition in culture. This suggests that a downregulation of the Notch1 pathway might be required to allow OPCs to enter terminal differentiation. We also provide evidence that OPCs and OLs express the Numb gene, a known negative regulator of Notch1 activity. In vivo, Numb was found in postnatal OLs from cerebellar and cerebral white matter. In vitro, Numb expression showed to be inversely correlated to that of Notch1, with higher levels of Numb proteins in mature OLs, in association with myelin-like membranes.
Insights
Notch1 signaling regulates oligodendrocyte maturation and central nervous system myelination. Numb, a negative regulator, is upregulated in mature oligodendrocytes, suggesting a mechanism for controlling Notch1 activity during development.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- The Notch1 pathway is crucial for cell fate determination in the central nervous system (CNS), particularly in regulating neural cell differentiation.
- In oligodendrocytes (OLs), Notch1 activity inhibits terminal maturation, impacting CNS myelination. Mechanisms controlling Notch1 gene expression and intracellular activity in OLs are not well understood.
Purpose of the Study:
- To investigate the developmental regulation of Notch1 gene expression in OLs.
- To explore how OLs control Notch1 pathway activity and its impact on oligodendrocyte differentiation and myelination.
Main Methods:
- Quantitative analysis of Notch1 gene expression in proliferative OL progenitor cells (OPCs) versus mature OLs.
- In vitro experiments using Delta1 (Notch1 activator) and thyroid hormone to assess their effects on OPC differentiation.
- In vitro and in vivo assessment of Numb gene expression in OPCs and OLs, correlating it with Notch1 levels and myelin formation.
Main Results:
- Notch1 gene expression is developmentally regulated, being higher in proliferative OPCs and decreasing upon maturation.
- Delta1-mediated Notch1 activation overrides differentiation signals like thyroid hormone, suggesting Notch1 downregulation is necessary for terminal differentiation.
- Numb, a negative regulator of Notch1, is expressed in OPCs and OLs, with its expression inversely correlated to Notch1 levels and increasing in mature OLs associated with myelin.
Conclusions:
- Oligodendrocyte differentiation and CNS myelination are controlled by the developmental regulation of Notch1 signaling.
- The Numb gene acts as a negative regulator of Notch1 activity in OLs, with its upregulation in mature cells potentially facilitating terminal differentiation and myelination.