Genetic analysis of forebrain patterning and neurogenesis

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date4/1/062/28/19

ASJC

  • Genetics
  • Cell Biology

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