Brain-Derived Neurotrophic Factor (BDNF) has Proliferative Effects on Neural Stem Cells through the Truncated TRK-B Receptor, MAP Kinase, AKT, and STAT-3 Signaling Pathways

Abstract

Neurospheres can be generated from the mouse fetal forebrain by exposing multipotent neural stem cells (NSCs) to epidermal growth factor (EGF). In the presence of EGF, NSCs can proliferate continuously while retaining the potential to differentiate into neurons, astrocytes and oligodendrocytes. We examined the expression pattern of the neurotrophin (NT) receptors tropomysin-related kinase (TRK)-A, TRK-B, TRK-C and p75 neurotrophin receptor (p75(NTR)) in NSCs and the corresponding lineage cells. Furthermore, we analyzed the action of the NT Brain-Derived Neurotrophic Factor (BDNF) on NSCs' behavior. The effects of BDNF on NSC proliferation and differentiation were examined together with the signaling pathways by which BDNF receptors transduce signaling effects. We found that all the known NT receptors, including the truncated isoforms of TRK-B (t-TRK-B) and TRK-C (t-TRK-C), were expressed by Nestin-positive cells within the neurosphere. Proliferation was enhanced in Nestin-positive and BrdU-positive cells in the presence of BDNF. In particular, we show that t-TRK-B was abundantly expressed in NSCs and the corresponding differentiated glia cells while full length TRK-B (fl-TRK-B) was expressed in fully differentiated post-mitotic neurons such as the neuronal cells of the newborn mouse cortex, suggesting that BDNF may exert its proliferative effects on NSCs through the t-TRK-B receptor. Finally, we analyzed the cell fates of NSCs differentiated with BDNF in the absence of EGF and we demonstrate that BDNF stimulated the formation of differentiated cell types in different proportions through the MAP kinase, AKT and STAT-3 signaling pathways. Thus, the in-vivo regulation of neurogenesis may be mediated by the summation of signals from the BDNF receptors, in particular the t-TRK-B receptor, regulating physiological fates as diverse as normal neural replacement, excessive neural loss, or tumor development.

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“…Due to this overall proliferative effect of BDNF on NSCs, the actual transfection efficiency reported here is therefore likely to be an underestimate of the initial transfection levels. The result here demonstrates the functional effects of the encoded BDNF as it is known to be involved in NSC proliferation, among many other cellular processes such as neural differentiation and maturation [40]. Our study shows that the BDNF levels induced are sufficient to have a functional biological effect on NSCs.…”

“…As an example, transplantation of a mixed population of VEGF-engineered NSCs (transduction efficiency of ca 20-30% obtained in this study) demonstrated neuroprotective effects and increased angiogenesis in intact non-disease brains [41]. The proliferative effects of BDNF on NSCs can be predicted to be advantageous for ex vivo gene therapy, resulting in genesis of increased numbers of progenitor populations that can in turn result in enhanced production of neurons [40]. While such enhanced division does…”

A small molecule p75NTR ligand protects neurogenesis after traumatic brain injury

“…A small population of BrdU1 cells remains unaccounted for by newly formed neurons and astrocytes suggesting that LM11A-31 promotes proliferation/survival of other cell populations; the delineation of these and determination of their roles in recovery will be the subject of future studies. Finally, it is of interest that BDNF, which has been implicated as a significant factor in TBI recovery [69] and may have direct [70] and indirect [71] effects on neural progenitors via TrkB-family receptors, was divergent from LM11A-31 and NGF in its effects on Figure 7. Controlled cortical impact (CCI) and LM11A-31 effects on spatial memory performance.…”

<i>Gastrodia elata</i> modulates amyloid precursor protein cleavage and cognitive functions in mice

“…The CellTiter-Glo ® Luminescent Cell Viability Assay (Promega, Madison, WI, USA) and the fluorescein isothiocyanate (FITC) 5-bromo-2'-deoxyuridine (BrdU) Flow Kit (BD Biosciences, Franklin Lakes, NJ, USA) were used to analyze cell proliferation as described previously (15). Briefly, the CellTiterGlo ® Luminescent Cell Viability Assay generates a luminescent signal based on the quantity of adenosine triphosphate (ATP) present in viable cells, which is proportional to the number of metabolically active cells.…”