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Gene Review

vnd  -  ventral nervous system defective

Drosophila melanogaster

Synonyms: CG6172, Dm vnd, Dm-NK2, Dmel\CG6172, EC6, ...
 
 
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Disease relevance of vnd

  • The ventral nervous system defective, or vnd, homeobox gene is expressed from cellularization throughout early neural development in ventral neuroectodermal cells, neuroblasts, and ganglion mother cells, and later in an unrelated pattern in neurons [1].
 

High impact information on vnd

  • Vertebrate genes closely related to vnd (Nkx2.1 and Nkx2.2), ind (Gsh1 and Gsh2), and msh (Msx1 and Msx3) are expressed in corresponding ventral, intermediate, and dorsal domains during vertebrate neurogenesis, raising the possibility that dorsoventral patterning within the central nervous system is evolutionarily conserved [2].
  • In Drosophila the central nervous system develops from three longitudinal columns of cells: ventral cells that express the vnd/nk2 homeobox gene, intermediate cells, and dorsal cells that express the msh homeobox gene [2].
  • Dorsoventral patterning in the Drosophila central nervous system: the vnd homeobox gene specifies ventral column identity [3].
  • We use molecular markers that distinguish ventral, intermediate, and dorsal column neuroectoderm and neuroblasts, and a cell lineage marker for selected neuroblasts, to show that loss of vnd transforms ventral into intermediate column identity and that specific ventral neuroblasts fail to form [3].
  • We discuss these findings within the framework of early Drosophila neurogenesis and the known phenotypes associated with the vnd locus [4].
 

Biological context of vnd

  • We have investigated the role of these genes (with special emphasis on the Nkx2-type homeobox gene vnd) in early embryonic development of the brain [5].
  • Understanding the mechanisms involved in patterning vnd, ind, and msh expression is important, because DV columnar homeobox gene expression in the neuroectoderm is an early, essential, and evolutionarily conserved step in generating neuronal diversity along the DV axis of the CNS [6].
  • For example, the misexpression of vnd in transgenic embryos represses ind and msh, and the addition of Vnd binding sites to a heterologous enhancer is sufficient to mediate repression [7].
  • More recently, the vnd locus has been implicated in the regulation of the proneural AS-C genes and the neurogenic genes of the Enhancer of split complex [4].
  • In this paper we report the identification of a transcript associated with the vnd locus, the transcript distribution in embryogenesis, which is compatible with the nervous system mutant phenotypes described for this gene, and that the protein product is a member of the NK-2 homeodomain family [4].
 

Anatomical context of vnd

  • We also show that, in the anterior brain (protocerebrum), normal production of early glial cells is independent from msh and vnd, in contrast to the posterior brain (deuto- and tritocerebrum) and to the ventral nerve cord [5].
  • The commissural defects seen in vnd gain-of-function mutants correlate with midline glial defects, whereas the mislocalization of interneurons coincides with longitudinal glial mis-specification [1].
  • In addition, another mesodermal NK2-type gene from Drosophila, bagpipe, which is normally only needed for visceral mesoderm but not heart development, cannot substitute for tinman at all [8].
  • We have previously described CEH-22, an NK-2 class homeodomain transcription factor similar to Drosophila tinman and vertebrate Nkx2-5, which is expressed exclusively in the pharyngeal muscles [9].
  • The NK-2 gene was shown to be activated by dorsal in the ventral half of the embryo during the syncytial blastoderm stage of development [10].
 

Associations of vnd with chemical compounds

 

Physical interactions of vnd

 

Regulatory relationships of vnd

  • First, vnd is required to activate proneural cluster formation within the medial column of every other neuroblast row through regulatory elements located 3' to ac; second, through a 5' regulatory region, vnd functions to increase or maintain proneural gene expression in the cell within the proneural cluster that normally becomes the neuroblast [13].
  • In vnd mutants, head neuroectoderm Nk6 expression is abolished where it is normally co-expressed with vnd [14].
  • High levels of DER activation in the ventralmost cells trigger expression of the transcription factors encoded by ventral nervous system defective (vnd) and pointed P1 (pntPl) [15].
 

Other interactions of vnd

  • Three mutants are deletions of conserved regions (i.e., tinman motif, acidic motif, and NK-2 box), and the fourth, Y54M vndNK-2, corresponds to a single amino acid residue replacement in the homeodomain [16].
  • Interaction between Drosophila EGF receptor and vnd determines three dorsoventral domains of the neuroectoderm [17].
  • We show genetically that Nk6 is positively regulated, directly or indirectly, by vnd in brain precursors [14].
  • The NK-2 gene is not expressed in the mesodermal anlage due to repression by snail, in mesectodermal cells due to repression by single-minded, or in the lateral neuroectodermal and/or dorsal epidermal anlagen due to repression mediated indirectly by decapentaplegic [10].
  • The DNase I footprinting analysis of Clone A with vnd/NK-2 homeodomain protein revealed three strong binding sites and one weak binding site between 15 and 130 bp of Clone A [12].
 

Analytical, diagnostic and therapeutic context of vnd

  • We further analyzed the interactions between Clone A and vnd/NK-2 homeodomain protein by mobility-shift assay, DNase I footprinting, methylation interference, and ethylation interference [12].
  • Thermodynamic parameters for vnd/NK-2 homeodomain proteins binding sequence-specific 18 bp DNA have been determined by isothermal titration calorimetry (10-30 degrees C) [18].

References

  1. Regulated vnd expression is required for both neural and glial specification in Drosophila. Mellerick, D.M., Modica, V. J. Neurobiol. (2002) [Pubmed]
  2. Dorsoventral patterning in the Drosophila central nervous system: the intermediate neuroblasts defective homeobox gene specifies intermediate column identity. Weiss, J.B., Von Ohlen, T., Mellerick, D.M., Dressler, G., Doe, C.Q., Scott, M.P. Genes Dev. (1998) [Pubmed]
  3. Dorsoventral patterning in the Drosophila central nervous system: the vnd homeobox gene specifies ventral column identity. McDonald, J.A., Holbrook, S., Isshiki, T., Weiss, J., Doe, C.Q., Mellerick, D.M. Genes Dev. (1998) [Pubmed]
  4. vnd, a gene required for early neurogenesis of Drosophila, encodes a homeodomain protein. Jiménez, F., Martin-Morris, L.E., Velasco, L., Chu, H., Sierra, J., Rosen, D.R., White, K. EMBO J. (1995) [Pubmed]
  5. Segment-specific requirements for dorsoventral patterning genes during early brain development in Drosophila. Urbach, R., Volland, D., Seibert, J., Technau, G.M. Development (2006) [Pubmed]
  6. Convergence of dorsal, dpp, and egfr signaling pathways subdivides the drosophila neuroectoderm into three dorsal-ventral columns. von Ohlen, T., Doe, C.Q. Dev. Biol. (2000) [Pubmed]
  7. Ventral dominance governs sequential patterns of gene expression across the dorsal-ventral axis of the neuroectoderm in the Drosophila embryo. Cowden, J., Levine, M. Dev. Biol. (2003) [Pubmed]
  8. Differential rescue of visceral and cardiac defects in Drosophila by vertebrate tinman-related genes. Park, M., Lewis, C., Turbay, D., Chung, A., Chen, J.N., Evans, S., Breitbart, R.E., Fishman, M.C., Izumo, S., Bodmer, R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. The Caenorhabditis elegans NK-2 homeobox gene ceh-22 activates pharyngeal muscle gene expression in combination with pha-1 and is required for normal pharyngeal development. Okkema, P.G., Ha, E., Haun, C., Chen, W., Fire, A. Development (1997) [Pubmed]
  10. Dorsal-ventral patterning genes restrict NK-2 homeobox gene expression to the ventral half of the central nervous system of Drosophila embryos. Mellerick, D.M., Nirenberg, M. Dev. Biol. (1995) [Pubmed]
  11. Distortion of the three-dimensional structure of the vnd/NK-2 homeodomain bound to DNA induced by an embryonically lethal A35T point mutation. Hwang, K.J., Xiang, B., Gruschus, J.M., Nam, K.Y., No, K.T., Nirenberg, M., Ferretti, J.A. Biochemistry (2003) [Pubmed]
  12. Identification and analysis of vnd/NK-2 homeodomain binding sites in genomic DNA. Wang, L.H., Chmelik, R., Tang, D., Nirenberg, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. The ventral nervous system defective gene controls proneural gene expression at two distinct steps during neuroblast formation in Drosophila. Skeath, J.B., Panganiban, G.F., Carroll, S.B. Development (1994) [Pubmed]
  14. Nk6, a novel Drosophila homeobox gene regulated by vnd. Uhler, J., Garbern, J., Yang, L., Kamholz, J., Mellerick, D.M. Mech. Dev. (2002) [Pubmed]
  15. EGF receptor signaling induces pointed P1 transcription and inactivates Yan protein in the Drosophila embryonic ventral ectoderm. Gabay, L., Scholz, H., Golembo, M., Klaes, A., Shilo, B.Z., Klämbt, C. Development (1996) [Pubmed]
  16. Mutations that affect the ability of the vnd/NK-2 homeoprotein to regulate gene expression: transgenic alterations and tertiary structure. Koizumi, K., Lintas, C., Nirenberg, M., Maeng, J.S., Ju, J.H., Mack, J.W., Gruschus, J.M., Odenwald, W.F., Ferretti, J.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Interaction between Drosophila EGF receptor and vnd determines three dorsoventral domains of the neuroectoderm. Yagi, Y., Suzuki, T., Hayashi, S. Development (1998) [Pubmed]
  18. The vnd/NK-2 homeodomain: thermodynamics of reversible unfolding and DNA binding for wild-type and with residue replacements H52R and H52R/T56W in helix III. Gonzalez, M., Weiler, S., Ferretti, J.A., Ginsburg, A. Biochemistry (2001) [Pubmed]
 
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