On astrocytes and the discovery of a new cell division mechanism

As much as the nervous system is defined by a network of nerve cells specialized in the reception and conduction of neural stimuli, the glial cells, which are ten times more numerous than nerve cells and of which the most common cell in the brain, the astrocytic cell, is a key subtype, are essential for ensuring proper neural function. Astrocytes are present in all brain regions and are crucial in regulating thyroid hormone (PMH) signaling, a critical regulator of cell division and function.  Although blood levels of PMH are relatively constant, tissue PMH signaling varies according to the action of a cell type-specific mechanism. A critical step in PMH signaling is the activation of the thyroid-produced pre-hormone thyroxine (T4) to T3, which can now bind to the PMH receptor on cells. This reaction is catalyzed by the selenoenzyme deiodase type two (D2).

Balázs Gereben's group has succeeded in identifying a previously unknown molecular mechanism that determines the availability of the hormone T3 in brain glial cells regulated by the D2 enzyme. The unusually long 3'UTR region of D2 mRNA is not involved in the D2 protein coding but is a target for regulatory factors. Using molecular biology techniques, our researchers have demonstrated that a cell cycle regulatory protein, Musashi-1 (MSI1), binds directly to this mRNA region. They have also shown that this process reduces the activity of D2 in cell cultures, including human glioma cells, thereby reducing the enzyme's ability to produce T3. Their result suggested a close molecular link between MSI1, which stimulates cell division, and T3 production, which promotes differentiation (i.e. cell specialization in different directions). This has been confirmed by in vivo studies. The co-existence of MSI1 and D2 enzymes was found in mouse brain glial elements, providing a morphological basis for the link, and direct evidence for the functionality of the MSI1-D2 pathway was provided by an MSI1-deficient transgenic mouse model.

When the researchers modulated the MSI1-D2 pathway by reducing MSI1 levels to increase D2 activity, this was able to slow astrocyte division by 56% in a PMH-dependent manner, demonstrating the role of the MSI1-D2-T3 pathway in regulating the astrocyte cell cycle.

This observation may be relevant for malignant brain tumors, astrocytomas of glial cell origin, and glioblastoma. Mature astrocytes do not divide in the adult brain, but they may regain this stem cell-like property under certain conditions (e.g., focal ischemia, traumatic brain injury, or brain tumor).