Abstract
Tyro3, Axl and Mertk (TAM) receptor tyrosine kinases play multiple functional roles by either providing intrinsic trophic support for cell growth or regulating the expression of target genes that are important in the homeostatic regulation of immune responses. TAM receptors have been shown to regulate adult hippocampal neurogenesis by negatively regulation of glial cell activation in central nervous system (CNS). In the present study, we further demonstrated that all three TAM receptors were expressed by cultured primary neural stem cells (NSCs) and played a direct growth trophic role in NSCs proliferation, neuronal differentiation and survival. The cultured primary NSCs lacking TAM receptors exhibited slower growth, reduced proliferation and increased apoptosis as shown by decreased BrdU incorporation and increased TUNEL labeling, than those from the WT NSCs. In addition, the neuronal differentiation and maturation of the mutant NSCs were impeded, as characterized by less neuronal differentiation (β-tubulin III+) and neurite outgrowth than their WT counterparts. To elucidate the underlying mechanism that the TAM receptors play on the differentiating NSCs, we examined the expression profile of neurotrophins and their receptors by real-time qPCR on the total RNAs from hippocampus and primary NSCs; and found that the TKO NSC showed a significant reduction in the expression of both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), but accompanied by compensational increases in the expression of the TrkA, TrkB, TrkC and p75 receptors. These results suggest that TAM receptors support NSCs survival, proliferation and differentiation by regulating expression of neurotrophins, especially the NGF.
Highlights
Neurogenesis takes place in adult central nervous system in many vertebrates including human [1]
While all three proteins were negligibly seen from the triple knockout (TKO) cells, they were clearly expressed in the WT neural stem cells (NSCs) with the strongest signal given by Tyro3 (Fig. 1A)
Expression of all three receptors in NSCs was further confirmed by immunocytochemistry, in which the specific antibodies against Tyro3, Axl and Mertk, positively labeled the WT NSCs (Fig. 1B) but not the TKO NSCs (Fig. 1C)
Summary
Neurogenesis takes place in adult central nervous system in many vertebrates including human [1]. The glial fibrillary acidic protein (GFAP)-positive radial glia-like cells in those regions are considered as primary stem cells normally remaining in the quiescent state, but have capacity for self-renewal and multipotential differentiation Once activated, they develop into proliferating intermediate progenitor cells and the undifferentiated neuroblasts that will further maturate into dentate granule cells in hippocampus or interneurons in the olfactory bulb, [3, 4]. They develop into proliferating intermediate progenitor cells and the undifferentiated neuroblasts that will further maturate into dentate granule cells in hippocampus or interneurons in the olfactory bulb, [3, 4] These newly generated neurons are capable to incorporate into the existing neural circuitry and contribute to brain functions [5]. Infection and the invoked inflammation inhibit NSC proliferation and neuronal differentiation [8, 13]
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