Fibroblast Growth Factors (FGFs) are critical for a vast array of developmental processes, including many aspects of brain development. How FGFs induce cell fates in one context, and promote proliferation, migration, differentiation, or survival in another is unknown. One possibility is that different intracellular signal transduction pathways are activated by FGFs in different cells. Based almost exclusively on biochemical and cell culture data, several intracellular transducers of FGF receptor activation have been proposed. Most accepted among these are the FGF Receptor Substrate (FRS) proteins, of which there are two family members. However, whether FRS is required for any FGF signaling in vivo remains unknown. Surprisingly, our preliminary data indicate that FRS is only required for certain aspects of FGF signaling in early telencephalon development. Hence in Aim 1, we examine the role of FRS in transducing FGF signals in vivo during telencephalon development. We are focusing on two processes of telencephalon development that we have previously shown require FGFs. By abolishing FGF signaling with a triple FGF receptor knockout, we found that FGFs are essential early for telencephalic cell survival and later for inhibiting the stem to progenitor cell transition in cortical precursors. In each case, we will determine if FGF signaling depends on FRS. Another possible explanation for why cells respond differently to FGFs is that other extracellular factors modulate its effects. For example, we have found that FGFs, WNTs, and TGFbs interact to regulate cell survival and Cdkn1a transcription in the early telencephalon. These findings provide an in vivo context to decipher how a cell can integrate multiple signals before deciding to adopt a fate.
In Aim 2, we examine how the transcriptional regulation of Cdkn1a by extracellular signals affects cell fate. Moreover, FOXG1, whose expression is promoted by FGFs, can inhibit the binding of a SMAD complex to the promoter of Cdkn1a in cultured cells.
In Aim 3, we determine whether and how Foxg1 participates in regulating Cdkn1a transcription in early telencephalic cells in vivo and whether Foxg1, Smad4, and Cdkn1a genetically interact.
The Fibroblast Growth Factors (FGFs) are a family of secreted intercellular signals. They are critical for a vast array of developmental processes, including many aspects of brain development. However, it remains a mystery how these factors promote different aspects of brain development, in some cases specifying different cell types and in other cases promoting proliferation, migration, differentiation, or survival of neural cells There are two likely explanations for this, which we explore with the proposed experiments. The first is that the intracellular machinery that responds to the FGFs is different in different cells The second is that other extracellular factors modulate a cell's response to FGFs. Neither of these possibilities has previously been adequately examined. We must understand how FGFs exert their different effects before we can begin to use pharmaceuticals in a rational way to treat FGF-related disorders, of which there are a growing number that affect brain development such as callosal agenesis, ventriculomegaly, spinocerebellar ataxia, myelitis, and craniosynostoses. In addition, a better understanding of how intracellularly machinery responds to extracellular signals will allow us to begin using FGFs for regenerative purposes by guiding the fates of cells in diseased brains.
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