EGFR Activates NFAT3 through Frequency Modulated Ca2+ Oscillations to Regulate the Proliferation of Transit-Amplifying (type C) Cells in the Adult SVZ

Abstract

Adult neurogenesis in the subventricular zone (SVZ) is a highly dynamic and finely-tuned process, subject to modulation by various physiological stimuli. Fast- dividing transit-amplifying (type C) cells are the immediate progeny of adult neural stem cells in the SVZ. These type C cells play a key role in neurogenesis by expanding cell numbers that eventually give rise to neuroblasts destined for the olfactory bulbs (OB). The size of the progenitor pool, and ultimately the number of neurons that engage in synaptic competition at the OB, is largely determined by the balance between proliferation and differentiation of these cells. Identifying the signalling mechanisms that regulate type C cell fate is an essential step towards understanding how intermediate progenitor pools are maintained in the adult neurogenic niches. A key feature of type C cells is their transient expression and activation of epidermal growth factor receptor (EGFR), which is a critical signal involved in regulating their undifferentiated and proliferative state in vitro, and in maintaining the number of neurons produced in vivo. EGFR activation leads to multiple complex signal transduction pathways, including Ca2+ liberation from the endoplasmic reticulum (ER). Biological systems can transduce information by initiating and/or altering the spatial and temporal dynamics of Ca2+ within the cell, allowing for distinct biological signals to be transmitted in a process known as Ca2+-encoding. In this study, the role Ca2+-encoding plays in EGFR signal transduction was examined.