Incidental Mutation 'P0026:Elf3'

• ID: 8227
• Institutional Source: Beutler Lab
• Gene Symbol: Elf3
• Ensembl Gene: ENSMUSG00000003051
• Gene Name: E74-like factor 3
• Synonyms: ESE-1, jen, ESX
• MMRRC Submission: 038279-MU
• Essential gene?: Probably essential (E-score: 0.900)
• Stock #: P0026 (G1)
• Status: Validated
• Chromosome: 1
• Chromosomal Location: 135181312-135186210 bp(-) (GRCm39)
• Type of Mutation: critical splice donor site (2 bp from exon)
• DNA Base Change (assembly): A to G at 135183711 bp (GRCm39)
• Zygosity: Heterozygous
• Ref Sequence: ENSEMBL: ENSMUSP00000139769
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000003135] [ENSMUST00000185752]
• AlphaFold: Q3UPW2
• Predicted Effect: probably null; Transcript: ENSMUST00000003135
• SMART Domains: Protein: ENSMUSP00000003135; Gene: ENSMUSG00000003051

Domain	Start	End	E-Value	Type
SAM_PNT	67	151	6.32e-30	SMART
low complexity region	230	241	N/A	INTRINSIC
AT_hook	264	276	1.29e0	SMART
ETS	292	379	6.11e-49	SMART

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000180981
• Predicted Effect: probably null; Transcript: ENSMUST00000185752
• SMART Domains: Protein: ENSMUSP00000139769; Gene: ENSMUSG00000003051

Domain	Start	End	E-Value	Type
SAM_PNT	47	131	1.36e-29	SMART
low complexity region	210	221	N/A	INTRINSIC
AT_hook	244	256	1.29e0	SMART
ETS	272	359	6.11e-49	SMART

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000188895
• Meta Mutation Damage Score: 0.9491
• Coding Region Coverage:
  • 1x: 85.6%
  • 3x: 78.9%
  • 10x: 59.5%
  • 20x: 38.1%
• Validation Efficiency: 97% (63/65)
• MGI Phenotype: PHENOTYPE: About one third of mice homozygous for a reporter allele die at E11.5; over half of those born develop a wasted phenotype, lethargy and watery diarrhea and die during the first few weeks of life exhibiting dysmorphogenesis and altered differentiation of small intestinal epithelium. [provided by MGI curators]
• Allele List at MGI:

  All alleles(3) : Targeted(3)

• Posted On: 2012-11-20
• Science Writer: Anne Murray

Protein Function and Prediction

Elf3 encodes an E26 transformation-specific (ETS) transcription factor.  The Ets transcription factors are often mediators of extracellular signaling pathways that regulate cell proliferation, differentiation, apoptosis, and cell-cell/cell-matrix interactions (1;2).  Elf3 is involved in embryonic epithelial differentiation (3). Elf3 controls intestinal epithelial differentiation during development by regulating the expression of TGFβRII in epithelial cells [(4;5); reviewed in (6)]. Elf3 is also involved in mediating vascular inflammation after induction by inflammatory cytokines and lipopolysaccharide in vascular smooth muscle cells, endothelial cells, and cells of the monocyte-macrophage lineage; induction is mediated by by NF-κB transactivation of the Elf3 promoter. Elf3 can bind to the p50 subunit of NF-κB, an ESE-1-binding site within the NOS2 promoter has been identified, and Elf3 is also a transcriptional mediator of angiopoietin-1 in inflammation (7;8).  In addition, Elf3 regulates allergic airway inflammation by regulating DC-driven T cell differentiation (9). Other proposed roles of Elf3 are terminal differentiation of the epidermal skin epithelium, mammary gland development and breast cancer, and lung development, regeneration, and cancer [reviewed in (10)].

Expression/Localization

Elf3 is highly expressed in epithelial-rich tissues such as stomach, small intestine, colon, pancreas, trachea, lung, kidney, salivary gland, prostate gland, mammary gland, uterus, and skin (11;12).

Background

Elf3^{tm1Pjh/tm1Pjh}; MGI:2662485

involves: 129S4/SvJae * C57BL/6

About one third of mice homozygous for a reporter allele die at E11.5; over half of those born develop a wasted phenotype, lethargy and watery diarrhea and die during the first few weeks of life exhibiting dysmorphogenesis and altered differentiation of small intestinal epithelium (3).  The impaired enterocyte and goblet cell differentiation can be rescued by transgenic TGFβRII expression in the intestinal epithelium (4) via direct stimulation of TGFβRII promotor activity (5).

Elf3^−/− mice: not clear if same model as above; not indicated in publication

Elf3^−/− mice were impaired in Th17 induction after epicutaneous sensitization and airway challenge with OVA (9). After epicutaneous sensitization, Elf3^−/− mice have impaired Th1 differentiation, which subsequently promotes Th2 differentiation (9).  IL-6 production in the OVA-challenged and -sensitized Elf3^−/− mice is impaired (9).  These mice exhibit increased maturation and migration of dendritic cells upon OVA sensitization (9).

References

  1. Wasylyk, B., Hagman, J., and Gutierrez-Hartmann, A. (1998) Ets Transcription Factors: Nuclear Effectors of the Ras-MAP-Kinase Signaling Pathway. Trends Biochem Sci. 23, 213-216.

  2. Sementchenko, V. I., and Watson, D. K. (2000) Ets Target Genes: Past, Present and Future. Oncogene. 19, 6533-6548.

  3. Ng, A. Y., Waring, P., Ristevski, S., Wang, C., Wilson, T., Pritchard, M., Hertzog, P., and Kola, I. (2002) Inactivation of the Transcription Factor Elf3 in Mice Results in Dysmorphogenesis and Altered Differentiation of Intestinal Epithelium. Gastroenterology. 122, 1455-1466.

  4. Flentjar, N., Chu, P. Y., Ng, A. Y., Johnstone, C. N., Heath, J. K., Ernst, M., Hertzog, P. J., and Pritchard, M. A. (2007) TGF-betaRII Rescues Development of Small Intestinal Epithelial Cells in Elf3-Deficient Mice. Gastroenterology. 132, 1410-1419.

  5. Choi, S. G., Yi, Y., Kim, Y. S., Kato, M., Chang, J., Chung, H. W., Hahm, K. B., Yang, H. K., Rhee, H. H., Bang, Y. J., and Kim, S. J. (1998) A Novel Ets-Related Transcription Factor, ERT/ESX/ESE-1, Regulates Expression of the Transforming Growth Factor-Beta Type II Receptor. J Biol Chem. 273, 110-117.

  6. Jedlicka, P., and Gutierrez-Hartmann, A. (2008) Ets Transcription Factors in Intestinal Morphogenesis, Homeostasis and Disease. Histol Histopathol. 23, 1417-1424.

  7. Rudders, S., Gaspar, J., Madore, R., Voland, C., Grall, F., Patel, A., Pellacani, A., Perrella, M. A., Libermann, T. A., and Oettgen, P. (2001) ESE-1 is a Novel Transcriptional Mediator of Inflammation that Interacts with NF-Kappa B to Regulate the Inducible Nitric-Oxide Synthase Gene. J Biol Chem. 276, 3302-3309.

  8. Brown, C., Gaspar, J., Pettit, A., Lee, R., Gu, X., Wang, H., Manning, C., Voland, C., Goldring, S. R., Goldring, M. B., Libermann, T. A., Gravallese, E. M., and Oettgen, P. (2004) ESE-1 is a Novel Transcriptional Mediator of Angiopoietin-1 Expression in the Setting of Inflammation. J Biol Chem. 279, 12794-12803.

  9. Kushwah, R., Oliver, J. R., Wu, J., Chang, Z., and Hu, J. (2011) Elf3 Regulates Allergic Airway Inflammation by Controlling Dendritic Cell-Driven T Cell Differentiation. J Immunol. 187, 4639-4653.

  10. Oliver, J. R., Kushwah, R., and Hu, J. (2012) Multiple Roles of the Epithelium-Specific ETS Transcription Factor, ESE-1, in Development and Disease. Lab Invest. 92, 320-330.

  11. Oettgen, P., Alani, R. M., Barcinski, M. A., Brown, L., Akbarali, Y., Boltax, J., Kunsch, C., Munger, K., and Libermann, T. A. (1997) Isolation and Characterization of a Novel Epithelium-Specific Transcription Factor, ESE-1, a Member of the Ets Family. Mol Cell Biol. 17, 4419-4433.

  12. Tymms, M. J., Ng, A. Y., Thomas, R. S., Schutte, B. C., Zhou, J., Eyre, H. J., Sutherland, G. R., Seth, A., Rosenberg, M., Papas, T., Debouck, C., and Kola, I. (1997) A Novel Epithelial-Expressed ETS Gene, ELF3: Human and Murine cDNA Sequences, Murine Genomic Organization, Human Mapping to 1q32.2 and Expression in Tissues and Cancer. Oncogene. 15, 2449-2462.