BTG2 - BTG2, Essential Regulator of Neuron Differentiation

BTG2, Essential Regulator of Neuron Differentiation

A number of studies in vivo have shown that BTG2 expression is associated with the neurogenic asymmetric division in neural progenitor cells. Moreover, when directly overexpressed in vivo in neural progenitor cells, BTG2 induces their differentiation. In fact, in the neuronal PC12 cell line BTG2 is not able to trigger differentiation by itself, but only to synergize with NGF, while in vivo BTG2 is fully able to induce differentiation of progenitor cells, i.e., during embryonic development in the neuroblast of the neural tube and in granule precursors of cerebellum, as well in adult progenitor cells of the dentate gyrus and of the subventricular zone. Notably, it has recently been shown that BTG2 is essential for the differentiation of new neurons, using a BTG2 knock out mouse. BTG2 is thus a pan-neural gene required for the development of the new neuron generated during adulthood, in the two neurogenic regions of adult brain, i.e., the hippocampus and the subventricular zone. Such requirement of BTG2 in neuron maturation is consistent with the fact that during brain development BTG2 is expressed in the proliferating neuroblasts of the ventricular zone of the neural tube, and to a lower extent in the differentiating neuroblasts of the mantle zone; postnatally it is expressed in cerebellar precursors mainly in the proliferating regions of the neuropithelium (i.e., in the external granular layer), and in the hippocampus in proliferating and differentiating progenitor cells. The pro-differentiative action of BTG2 appears to be consequent not only to inhibition of cell cycle progression but also to a BTG2-dependent activation of proneural genes in neural progenitor cells. In fact, BTG2 activates proneural genes by associating with the promoter of Id3, a key inhibitor of proneural gene activity, and by negatively regulating its activity.

BTG2 is a transcriptional cofactor, given that it has been shown to associate with, and regulate the promoters not only of Id3 but also of cyclin D1 and RAR-β, being part of transcriptional complexes. Interestingly, it has been shown that when the differentiation of new neurons of the hippocampus - a brain region important for learning and memory - is either accelerated or delayed by means of overexpression or deletion of BTG2, respectively, spatial and contextual memory is heavily altered. This suggests that the time the young neurons spend in different states of neuronal differentiation is critical for their ultimate function in learning and memory, and that BTG2 may play a role in the timing of recruitment of the new neuron into memory circuits.