The Action Of Activin And BFGF On The Differentiation Of Neuroal Stem Cells

Neuron metamorphic and necrotic desease caused by injury and denaturalization are difficult questions for the recent medical field, induction of stem cell differentiate into neural cell is a promising mathod for neural regeneration. Tyrosine hydroxylase (TH) is the first and major rate-limiting enzyme of catecholamine biosynthesis in DA and noradrenergic neurons (Nagatsu et al. 1964). CHAT is the key enzyme responsible for the synthesis of a neurotransmitter acetylcholine (ACh). Therefore, studies on the transcriptional regulation of TH and ChAT are very important for understanding the development of DA and acetylcholinergic neurons.Activin A, a member of the transforming growth factor (TGF)-βsuperfamily, has various effects on diverse biologic systems, such as erythroid differentiation, mesoderm induction in Xenopus embryos, bone growth and somatostatin induction (Mathews 1994, Tsuchida 2004). In addition, activin acts as a nerve cell survival factor (Schubert 1990) and has neurotrophic effects on nerve cells (Fann & Patterson 1994a,b, Hughes et al. 1999). Furthermore, activin A mRNA is expressed in the striatum during embryogenesis from E16–E17 (Roberts et al. 1991). Activin receptors are widely expressed in the adult rat brain, and their expression is upregulated in response to brain injury (Cameron et al. 1994, Funaba et al. 1997, Lewen et al. 1997).Fibroblast growth factor (FGF) is an important modulator of the cell growth and differentiation of various cells, including neurons. Basic FGF (bFGF) promotes survival and stimulates the neurite-promoting activity of embryonic DA neurons in the substantia nigra (Grothe et al. 2000). Recent research has revealed that all three bFGF isoforms and FGF receptors 1–3 are expressed in both the striatum and substantia nigra (Claus et al. 2004). Furthermore, bFGF produces the recovery of motor behavior, dopamine metabolite levels, striatal F-DOPA uptake and TH-positive cells in hemiparkinsonian monkeys (Fontan et al. 2002).Since activin A, bFGF and their receptors are expressed by a subpopulation of the ventricular zone progenitors, both activin and bFGF could exert their actions locally. However, the role of these factors in regulating the expression of catecholamine neurotransmitters and the molecular mechanisms involved in this process are not fully understood. Elucidating the mechanism of differentiation of TH-positive neurons in the striatum could provide insights for more effective therapeutic approaches for Parkinson's disease.In the present study, we report that activin A and basic fibroblast growth factor (bFGF) synergistically increased the protein level of tyrosine hydroxylase (TH), and also greatly increased the TH mRNA level, in both mouse E14 striatal primary cell cultures and the hippocampal neuronal cell line HT22. Activin A and bFGF cooperatively stimulated nuclear translocation of Smad3 and specifically activated ERK1/2, but not p38 or JNK. Interestingly, a specific inhibitor for MEK, U0126, efficiently blocked the induction of TH promoter activity by activin A and bFGF, indicating that activin A collaborated with bFGF signaling to induce the TH gene through selective activation of ERK-type MAP kinase in mouse striatal and HT22 cells. These data suggest that activin A may act in concert with bFGF for the development of TH-positive neurons.