ABSTRACT
Restrictions in neuronal fate occur during the transition from a multipotential to a postmitotic cell. This and later steps in neuronal differentiation are determined by extracellular signals. We report that basic fibroblast growth factor is mitogenic for stem cells and is a differentiation factor for calbindin-expressing hippocampal neurons. The neurotrophin NT-3 is a differentiation factor for the same neurons but does not affect proliferation. NT-3 and brain-derived neurotrophic factor promote the maturation of neurons derived from stem cells that have been grown in vitro. These results define functions for basic fibroblast growth factor and neurotrophins in the differentiation processes that direct a multipotential stem cell to a specific neuronal fate.
Subject(s)
Fibroblast Growth Factor 2/pharmacology , Hippocampus/cytology , Nerve Growth Factors/pharmacology , Nerve Tissue Proteins/pharmacology , Neurons/drug effects , Animals , Biomarkers , Brain-Derived Neurotrophic Factor , Calbindins , Cell Count , Cell Differentiation/drug effects , Cells, Cultured/cytology , Cells, Cultured/drug effects , Hippocampus/drug effects , Nerve Tissue Proteins/drug effects , Neurons/cytology , Neurotrophin 3 , Rats , Rats, Sprague-Dawley , S100 Calcium Binding Protein G/drug effects , Stem Cells/cytology , Stem Cells/drug effectsABSTRACT
The expression of the neurotrophins and trk receptors in the hippocampus has directed attention toward their roles in the development and maintenance of this region. We have examined the effects of the neurotrophins NT-3, BDNF, and NGF in cultures of developing rat hippocampal cells by two criteria: rapid induction of c-fos and neurotrophic responses. The selective induction of c-fos mRNA suggests the presence of functional receptors for NT-3 and BDNF, but not NGF, in embryonic hippocampal cultures. The NT-3-responsive cells were localized in pyramidal neurons of areas CA1 through CA3 and dentate granular and hilar cells of postnatal organotypic slices, as detected by c-Fos immunocytochemistry. In addition to immediate early responses, NT-3 caused a 10-fold increase in the number of cells expressing the neuronal antigen calbindin-D28k. This increase was dose dependent, with maximal stimulation at 10 ng/ml. In contrast, BDNF elicited small but significant calbindin responses. These results indicate biological responses to NT-3 in the CNS and suggest roles for for this neurotrophin during hippocampal neurogenesis.
