Neuregulin-1 increases the proliferation of neuronal progenitors from embryonic neural stem cells

Neuregulins are a family of proteins expressed in the developing brain and in brain regions that continue to undergo neurogenesis in adult animals. We investigated the effects of neuregulins on embryonic neural stem cells (NSCs) isolated from E11 mouse telencephalon. Treatment of basic fibroblast growth factor (bFGF)-expanded neurosphere cultures with the EGF-like domain of neuregulin1-beta1 (NRG-1(177-244)) resulted in a 4-fold increase of bromodeoxyuridine (BrDU)-labeled cells, suggesting that NRG-1 stimulated proliferation. The majority of the BrdU-positive cells co-labeled with an antibody against MAP2, indicating that the proliferating cells were neuronal. No BrDU labeling was seen in GFAP- or O4-positive cells. In NRG-1-treated cultures, many of the MAP2-positive cells co-labeled with an anti-nestin antibody, suggesting that these cells are neuron-restricted progenitors (NRPs). Few MAP2/nestin-positive cells were seen in control cultures. The increase in the number of neuronal cells in NRG-1-treated cultures was due to increased proliferation of MAP2-positive cells rather than the regulation of cell survival or fate determination. These results suggest that neuregulins are mitogenic to NRPs, thus endogenous neuregulins may play important roles during CNS neurogenesis.