Noggin and Wnt3a enable BMP4-dependent differentiation of telencephalic stem cells into GluR-agonist responsive neurons

• Published in: Molecular and cellular neuroscience Vol. 47; no. 1; pp. 10 - 18
• Main Authors: Andersson, Therese, Duckworth, Joshua K., Fritz, Nicolas, Lewicka, Michalina, Södersten, Erik, Uhlén, Per, Hermanson, Ola
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2011
• Subjects: Animals; Astrocytes; Bone morphogenetic protein 4; Bone Morphogenetic Protein 4 - metabolism; Bone morphogenetic proteins; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell culture; Cell Differentiation - physiology; Cells, Cultured; Culture Media, Conditioned - chemistry; Differentiation; Excitatory Amino Acid Agonists - metabolism; Gene Expression Profiling; Glutamic acid receptors; Medicin och hälsovetenskap; Mesenchyme; Mesoderm - cytology; Mesoderm - physiology; Microarray Analysis; Nervous system; Neural differentiation; Neural stem cell; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - physiology; Neuron; Neurons; Neurons - cytology; Neurons - physiology; Noggin protein; Rats; Rats, Sprague-Dawley; Receptors, Glutamate - metabolism; Stem cell plasticity; Stem cells; Telencephalon; Telencephalon - cytology; Wnt protein; Wnt Proteins - metabolism; Wnt3 Protein; Cell culture; Neuron; Neural differentiation; Astrocytes; Stem cell plasticity; Neural stem cell
• ISSN: 1044-7431; 1095-9327; 1095-9327
• DOI: 10.1016/j.mcn.2011.01.006

Early telencephalic development is dependent on the spatially and temporally coordinated regulation by essential signaling factors. For example, members of the Bone Morphogenetic Protein (BMP) family, such as BMP4, are crucial for proper development of dorsal telencephalic structures. Stimulation of multipotent telencephalic neural stem cells (NSCs) with BMP4 induces differentiation primarily into astrocytic and mesenchymal cells. However, BMP4-mediated mesenchymal differentiation is inhibited at certain culture conditions of NSCs, corresponding to in vivo developmental contexts. These inhibitory mechanisms are not fully understood and the terminal fate of non-astrocytic BMP4 treated NSCs under these conditions is unclear. Here we show that secreted factors inhibited BMP4-mediated mesenchymal differentiation of telencephalic NSCs. BMP4 mediated a dramatic and direct up-regulation of endogenous noggin levels, that in turn exerted a concentration-dependent inhibition of BMP4-mediated mesenchymal differentiation of NSCs. Instead, BMP4 exposure of NSCs induced neuronal differentiation in mesenchyme-preventing conditions, whereas treatment with recombinant noggin alone did not. Wnt signaling is known to be essential for the development of neurons derived from the dorsal telencephalon, and co-stimulation of NSCs with BMP4 + Wnt3a resulted in a synergistic effect yielding significantly increased number of mature neurons compared to stimulation with each factor alone. Thus whereas only a subset of BMP4-induced neurons derived from telencephalic NSCs, responded to glutamate receptor (GluR) agonists, over 80% of BMP4 + Wnt3a-induced neurons responded appropriately to GluR-agonists. Our results increase the understanding of the role for BMP4 in differentiation of telencephalic multipotent progenitors, and reveal novel implications for noggin and Wnt3a in these events.