Identification and characterization of FGF target genes

Division Of Basic Sciences - Nci

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Abstract

To address the deficiency in our knowledge of what genes respond to FGF signaling, we have an ongoing project to molecularly define FGF targets genes, as well as their function and regulation. In past work, we and others have identified the transcription factors encoded by Gbx1 and Gbx2 as FGF targets. Recently we investigated the functional relationship between Gbx family members in the developing spinal cord using combinatorial Gbx mouse mutants. We showed that each Gbx gene is upregulated if the other is absent. Additionally, Gbx genes regulate development of a subset of PAX2+ dorsal inhibitory interneurons. Also, expansion of proliferative cells into the anatomically defined mantle zone occurs in Gbx mutants. Lastly, our data shows a marked increase in apoptotic cell death in the ventral spinal cord of Gbx mutants during mid-embryonic stages. While our studies reveal that both members of the Gbx gene family are involved in development of subsets of PAX2+ dorsal interneurons and survival of ventral motor neurons, Gbx1 and Gbx2 are not sufficient to genetically compensate for the loss of one another. Thus, our studies provide novel insight to the relationship harbored between Gbx1 and Gbx2 in spinal cord development (J Dev Biol. 2020. PMID: 32244588). In current work, we demonstrate that the Hes7 transcriptional repressor is apparently a direct target of Fgf4 signaling. During vertebrate development, the presomitic mesoderm (PSM) is periodically segmented into somites, which will form the segmented vertebral column and associated muscle, connective tissue, and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. We examined mouse mutants lacking only Fgf4 or Fgf8, which we previously demonstrated act redundantly to prevent PSM differentiation. Fgf8 is not required for somitogenesis, but Fgf4 mutants display a range of vertebral defects. Analyzing gene expression with spatial model-based quantification of mRNAs fluorescently labeled by hybridization chain reaction, we show that FGF4 controls Notch pathway oscillations through the transcriptional repressor, HES7. We support this hypothesis by demonstrating a genetic synergy between Hes7 and Fgf4, but not with Fgf8. Thus, we establish Fgf4 as an essential Notch oscillation regulator and potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations. (eLife 2020 Nov 19;9:e55608. doi: 10.7554/eLife.55608.) Future work focuses on what regulatory elements within the Hes7 gene are responsive to Fgf4 signals.