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Gene Review

En2  -  engrailed 2

Mus musculus

Synonyms: BB131122, En-2, Homeobox protein en-2, Homeobox protein engrailed-2, Mo-En-2
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Disease relevance of En2


Psychiatry related information on En2

  • Deficits in social behavior were detected in En2(-/-) mice across maturation that included decreased play, reduced social sniffing and allogrooming, and less aggressive behavior [4].

High impact information on En2

  • To assess HNF-3 beta function, the gene has been ectopically expressed in the midbrain/hindbrain of transgenic embryos using an En-2 promoter/enhancer [5].
  • This corresponds to the region where two transcription factors encoded by the mouse engrailed genes (En-1 and En-2) are normally expressed [6].
  • Production of a mutation in mouse En-2 gene by homologous recombination in embryonic stem cells [7].
  • Our hybridization analysis in situ has revealed that expression of En-2 is restricted to a specific domain of the developing central nervous system from 8 days of development on, indicating a role for the gene in establishing spatial domains in the brain [7].
  • Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2 [8].

Biological context of En2

  • In mutant mice homozygous null for En1 and En2, the neurons are generated in the ventral midbrain, become postmitotic, and begin to express their neurotransmitter phenotype [9].
  • The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner [1].
  • A minimum En-2 1.0 kb enhancer fragment was defined and found to contain multiple positive and negative regulatory elements that function in concert to establish the early embryonic mid-hindbrain expression [10].
  • Engrailed-2 also affects the transient mediolateral (M/L) pattern of En-1 and Wnt-7b expression seen in late embryogenesis [11].
  • We have examined three markers of cerebellar compartmentation in En-2 mutant mice: the Zebrin II and Ppath monoclonal antibodies and the transgene L7lacZ [11].

Anatomical context of En2

  • The En2 knock-out mouse harbors cerebellar abnormalities that are similar to those found in autistic individuals and, as we report here, has a distinct anterior shift in the position of the amygdala in the cerebral cortex [12].
  • Null alleles of the mouse Engrailed-2 gene, a molecular homolog of the fly gene engrailed, have demonstrable effects on the anteroposterior (A/P) patterning of cerebellum as reflected in the disruption of the normal process of foliation of the cerebellar cortex and the alteration of transgene expression boundaries in the adult [11].
  • In mammals, two engrailed homologues exist, engrailed-1 and engrailed-2, which are expressed in a broad band around the isthmus at an age when the serotonergic and noradrenergic neurons in mid/hindbrain are generated [13].
  • Antisense targeting of En-2 expression of early somite stages produced few alterations in development, although approximately one third of the embryos exhibited a series of lateral folds in the spinal cord at the level of the forelimb-bud.(ABSTRACT TRUNCATED AT 250 WORDS)[14]
  • Selective disruption of "late onset" sagittal banding patterns by ectopic expression of engrailed-2 in cerebellar Purkinje cells [15].

Associations of En2 with chemical compounds

  • Moreover, we also show that there is a correlation between the M-L clusters established by the birth date-related Purkinje cells and the domains of engrailed-2, Wnt-7B, L7/pcp2, and EphA4 receptor tyrosine kinase expression [16].
  • Nontumorigenic mammary cell lines engineered to ectopically express En-2 have a marked reduction in their cycling time, lose cell contact inhibition, become sensitive to 17-AAG treatment, fail to differentiate when exposed to lactogenic hormones and induce mammary tumors when transplanted into cleared mammary glands of syngeneic hosts [17].

Physical interactions of En2

  • The two Pax2/5/8-binding sites were deleted from the En2 locus and replaced with the bacterial neo gene by homologous recombination in mouse embryonic stem cells [18].

Regulatory relationships of En2


Other interactions of En2

  • These results indicate the existence of a molecular hierarchy in which FGF8 signalling establishes the graded expression of En-2 within the tectum [22].
  • In interspecific crosses, the segregation of either mutation was followed in relation to polymorphic alleles of Msx1, Il6, and En2, to give a fine map around the mutant loci [23].
  • Our experiments show that the interaction between these two proteins is required for the positioning of the isthmic organizer genes Fgf8, Pax2 and En2 [24].
  • En-2 enhancer activity in the first arch requires a combination of cis-acting sequences that includes a motif which is identical to one found in the Otx2 enhancer and which is sufficient to direct expression in the first arch [25].
  • Shh mapped to a position 0.6 cM distal to En2 and 1.9 cM proximal to Il6 on mouse chromosome 5 [26].

Analytical, diagnostic and therapeutic context of En2

  • Significantly, no change in the Engrailed-2 mutant phenotype occurs after a similar background switch, and whole-mount in situ hybridization reveals identical En2 expression patterns in wild-type C57BL/6J and 129/Sv mice [27].
  • To determine whether these contrasting phenotypes reflect differences in temporal expression or biochemical activity of the En proteins, En-1 coding sequences were replaced with En-2 sequences by gene targeting [8].
  • When grafted ectopically into the diencephalon of a chick host embryo, a portion of met-mesencephalon straddling the met-mesencephalic constriction has the capacity to induce En-2 expression in the surrounding host tissue [28].
  • The antiserum detects both the En-1 and En-2 proteins in mouse, chick and Xenopus embryos by Western blot analysis [29].


  1. Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice. Sgad??, P., Alb??ri, L., Gherbassi, D., Galasso, S.L., Ramakers, G.M., Alavian, K.N., Smidt, M.P., Dyck, R.H., Simon, H.H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Retroviral misexpression of engrailed genes in the chick optic tectum perturbs the topographic targeting of retinal axons. Friedman, G.C., O'Leary, D.D. J. Neurosci. (1996) [Pubmed]
  3. Overexpression of Pax5 is not sufficient for neoplastic transformation of mouse neuroectoderm. Steinbach, J.P., Kozmik, Z., Pfeffer, P., Aguzzi, A. Int. J. Cancer (2001) [Pubmed]
  4. En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Cheh, M.A., Millonig, J.H., Roselli, L.M., Ming, X., Jacobsen, E., Kamdar, S., Wagner, G.C. Brain Res. (2006) [Pubmed]
  5. HNF-3 beta as a regulator of floor plate development. Sasaki, H., Hogan, B.L. Cell (1994) [Pubmed]
  6. Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development. Danielian, P.S., McMahon, A.P. Nature (1996) [Pubmed]
  7. Production of a mutation in mouse En-2 gene by homologous recombination in embryonic stem cells. Joyner, A.L., Skarnes, W.C., Rossant, J. Nature (1989) [Pubmed]
  8. Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2. Hanks, M., Wurst, W., Anson-Cartwright, L., Auerbach, A.B., Joyner, A.L. Science (1995) [Pubmed]
  9. Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors. Simon, H.H., Thuret, S., Alberi, L. Cell Tissue Res. (2004) [Pubmed]
  10. Two Pax-binding sites are required for early embryonic brain expression of an Engrailed-2 transgene. Song, D.L., Chalepakis, G., Gruss, P., Joyner, A.L. Development (1996) [Pubmed]
  11. Pattern deformities and cell loss in Engrailed-2 mutant mice suggest two separate patterning events during cerebellar development. Kuemerle, B., Zanjani, H., Joyner, A., Herrup, K. J. Neurosci. (1997) [Pubmed]
  12. The mouse Engrailed genes: A window into autism. Kuemerle, B., Gulden, F., Cherosky, N., Williams, E., Herrup, K. Behav. Brain Res. (2007) [Pubmed]
  13. Engrailed genes control developmental fate of serotonergic and noradrenergic neurons in mid- and hindbrain in a gene dose-dependent manner. Simon, H.H., Scholz, C., O'Leary, D.D. Mol. Cell. Neurosci. (2005) [Pubmed]
  14. Antisense inhibition of engrailed genes in mouse embryos reveals roles for these genes in craniofacial and neural tube development. Augustine, K.A., Liu, E.T., Sadler, T.W. Teratology (1995) [Pubmed]
  15. Selective disruption of "late onset" sagittal banding patterns by ectopic expression of engrailed-2 in cerebellar Purkinje cells. Baader, S.L., Vogel, M.W., Sanlioglu, S., Zhang, X., Oberdick, J. J. Neurosci. (1999) [Pubmed]
  16. Mediolateral compartmentalization of the cerebellum is determined on the "birth date" of Purkinje cells. Hashimoto, M., Mikoshiba, K. J. Neurosci. (2003) [Pubmed]
  17. EN2 is a candidate oncogene in human breast cancer. Martin, N.L., Saba-El-Leil, M.K., Sadekova, S., Meloche, S., Sauvageau, G. Oncogene (2005) [Pubmed]
  18. Two Pax2/5/8-binding sites in Engrailed2 are required for proper initiation of endogenous mid-hindbrain expression. Li Song, D., Joyner, A.L. Mech. Dev. (2000) [Pubmed]
  19. A gene with sequence similarity to Drosophila engrailed is expressed during the development of the neural tube and vertebrae in the mouse. Davidson, D., Graham, E., Sime, C., Hill, R. Development (1988) [Pubmed]
  20. Fate of midbrain dopaminergic neurons controlled by the engrailed genes. Simon, H.H., Saueressig, H., Wurst, W., Goulding, M.D., O'Leary, D.D. J. Neurosci. (2001) [Pubmed]
  21. Engrailed-2 negatively regulates the onset of perinatal Purkinje cell differentiation. Jankowski, J., Holst, M.I., Liebig, C., Oberdick, J., Baader, S.L. J. Comp. Neurol. (2004) [Pubmed]
  22. Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. Lee, S.M., Danielian, P.S., Fritzsch, B., McMahon, A.P. Development (1997) [Pubmed]
  23. Msx1 is close but not allelic to either Hm or Hx on mouse chromosome 5. Robert, B., Montagutelli, X., Houzelstein, D., Ferland, L., Cohen, A., Buckingham, M., Guénet, J.L. Mamm. Genome (1994) [Pubmed]
  24. The homeoprotein Xiro1 is required for midbrain-hindbrain boundary formation. Glavic, A., Gómez-Skarmeta, J.L., Mayor, R. Development (2002) [Pubmed]
  25. Cellular and cis-regulation of En-2 expression in the mandibular arch. Degenhardt, K., Rentschler, S., Fishman, G., Sassoon, D.A. Mech. Dev. (2002) [Pubmed]
  26. Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog. Marigo, V., Roberts, D.J., Lee, S.M., Tsukurov, O., Levi, T., Gastier, J.M., Epstein, D.J., Gilbert, D.J., Copeland, N.G., Seidman, C.E. Genomics (1995) [Pubmed]
  27. Factors in the genetic background suppress the engrailed-1 cerebellar phenotype. Bilovocky, N.A., Romito-DiGiacomo, R.R., Murcia, C.L., Maricich, S.M., Herrup, K. J. Neurosci. (2003) [Pubmed]
  28. Ectopic induction and reorganization of Wnt-1 expression in quail/chick chimeras. Bally-Cuif, L., Wassef, M. Development (1994) [Pubmed]
  29. Examining pattern formation in mouse, chicken and frog embryos with an En-specific antiserum. Davis, C.A., Holmyard, D.P., Millen, K.J., Joyner, A.L. Development (1991) [Pubmed]
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