Disease relevance of grh

• Further, we show that the predominant protein binding the purine-rich HTLV-I enhancer element in human T cells is not ets-1 but Elf-1, a member of the ets family which is very similar to the Drosophila morphogen E74 [1].

High impact information on grh

• Here we report the requirements for transcriptional activation directed by NTF-1, a developmentally regulated transcription factor in Drosophila [2].
• Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype [3].
• Binding sites for transcription factor NTF-1/Elf-1 contribute to the ventral repression of decapentaplegic [4].
• NTF-1 mRNA is synthesized during oogenesis and deposited in the developing oocyte where it is available to contribute to ventral repression during early embryogenesis [4].
• Interestingly, dTFIIA-L/S is also able to significantly enhance transcriptional activation by upstream transcription factors including Sp1, VP16, and NTF-1 [5].

Biological context of grh

• Developmental function of Elf-1: an essential transcription factor during embryogenesis in Drosophila [6].
• Analysis of the mutant phenotype indicates that Elf-1 coordinately regulates multiple genes involved in the differentiation of epidermal structures [6].
• This pathway includes a wound response enhancer from the Ddc gene that requires grainy head (grh) function and binding sites for the Grh transcription factor [7].
• In an effort to characterize sequence-specific transcription factors that regulate gene expression during Drosophila development, we identified and purified a novel DNA-binding activity (NTF-1) [8].
• A cDNA clone encoding the open reading frame of NTF-1 was isolated, and the deduced primary amino acid sequence of NTF-1 includes a glutamine-rich region reminiscent of the transcriptional activation domains found in Sp1 but no recognizable DNA-binding domain [8].

Anatomical context of grh

• The expression of Elf-1 during embryogenesis is restricted to nuclei of tissues derived from ectoderm, predominantly the central nervous system (CNS) and the epidermis [9].
• In the thorax, Grh prolongs neural proliferation by maintaining a mitotically active neuroblast [10].
• Functional domain studies in Drosophila Schneider cells and endothelial cells revealed examples of positive and negative protein-protein cooperativity involving Sp1, variants of Sp3, Ets-1, Elf-1, and MAZ [11].
• Here, we show that grh is essential for pNBs to adopt the stem cell programme appropriate to their position within the CNS [12].
• In contrast, in the context of the IL-2R alpha promoter, conversion of the naturally occurring low affinity Elf-1 site to an optimal site decreased inducible activation of a reporter construct in Jurkat cells [13].

Associations of grh with chemical compounds

• Drosophila tissue-specific transcription factor NTF-1 contains a novel isoleucine-rich activation motif [14].
• We show that a restricted selectivity for GGAA core-containing sites could be conferred to Ets1 upon changing a single lysine residue within CRIII to the threonine found in Elf1 and E74 at this position [15].
• Further, we demonstrated that although both Elf-1, an ets family member with significant similarity to the drosophila developmental regulatory protein E74, and Pu.1, a monocyte- and B-cell-specific member of the ets family, bind the purine-rich enhancer region, Elf-1 is the protein which binds predominantly in vivo [16].

Physical interactions of grh

• Moreover, grainyhead interacts genetically with pleiohomeotic in a transgene-based, pairing-dependent silencing assay [17].
• Binding of the RING polycomb proteins to specific target genes in complex with the grainyhead-like family of developmental transcription factors [18].
• The CP2-dinG interaction is conserved in evolution with the Drosophila factor grainyhead binding to dring, the fly homologue of dinG [18].

Regulatory relationships of grh

• Purified NTF-1 activates transcription in vitro in a binding site-dependent manner through upstream sequences of the Ubx promoter [8].
• Grainy head controls apical membrane growth and tube elongation in response to Branchless/FGF signalling [19].
• In the abdomen, Grh terminates neural proliferation by regulating the competence of neuroblasts to undergo apoptosis in response to Abdominal-A expression [10].

Other interactions of grh

• Previous studies have shown that overexpression of NTF-1 in the postblastoderm embryo results in a phenotype that is consistent with a role for this factor in the repression of dpp later in embryogenesis [4].
• We now demonstrate that the human PcG protein dinG interacts with CP2, a mammalian member of the grainyhead-like family of transcription factors, in vitro and in vivo [18].
• For example, NTF-1 plays a critical role in the tissue-specific expression of the Drosophila Dopa decarboxylase gene [14].
• We favour a two-step model for FGF in branching: first, induction of cell movement and apical membrane growth, and second, activation of Grainy head to limit lumen elongation, ensuring that branches reach and attain their characteristic lengths [19].
• The grainy head transcription factor is essential for the function of the frizzled pathway in the Drosophila wing [20].

Analytical, diagnostic and therapeutic context of grh

• In addition, in situ hybridization experiments revealed that NTF-1 is transcribed in a spatially restricted pattern in the embryo, with the highest level of expression observed in the epidermis and a subset of cells in the CNS [8].

References