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Gene Review

Mid1  -  midline 1

Mus musculus

Synonyms: 61B3-R, DXHXS1141, E3 ubiquitin-protein ligase Midline-1, Fxy, Midin, ...
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Disease relevance of Mid1


Psychiatry related information on Mid1

  • Static and dynamic views of retinal growth cones in this decision region reveal that extensive exploratory behavior and selective retraction of parts of the growing tips of uncrossed fibers, in response to cellular cues at the midline, is a major event in the guidance of these fibers [6].

High impact information on Mid1

  • Pathfinding of retinal ganglion cell (RGC) axons at the midline optic chiasm determines whether RGCs project to ipsilateral or contralateral brain visual centers, critical for binocular vision [7].
  • GAP-43-deficient retinal axons remain trapped in the chiasm for 6 days, unable to navigate past this midline decision point [8].
  • The transcription factor gene HNF-3 beta is expressed in the ventral midline of the mouse embryonic neural tube, including the floor plate, a structure important for dorsoventral patterning and axonal guidance [9].
  • Morphogenesis of the posterior midbrain was affected as early as embryonic day 16.5, leading to a reduction of the inferior colliculus near the midline and to altered foliation of the anterior cerebellum [10].
  • Early defects are observed in the establishment or maintenance of midline structures, such as the notochord and the floorplate, and later defects include absence of distal limb structures, cyclopia, absence of ventral cell types within the neural tube, and absence of the spinal column and most of the ribs [11].

Chemical compound and disease context of Mid1


Biological context of Mid1

  • Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome [17].
  • Cooperation of sonic hedgehog enhancers in midline expression [18].
  • The Fxy gene in mice is also located on the X chromosome but spans the pseudoautosomal boundary in this species [19].
  • During embryogenesis, induction of these and other ventral neurons is influenced by interactions with the induction of mesoderm of the notochord and the floor plate, which lies at the ventral midline of the developing CNS [20].
  • We investigated the consequences of the translocation further by sequencing exons and introns of Fxy in various rodent species [21].

Anatomical context of Mid1


Associations of Mid1 with chemical compounds

  • Evidence from labeling growing retinal axons with the carbocyanine dye Dil in mouse embryos indicates that the two subpopulations diverge at a zone along the midline of the optic chiasm [27].
  • We conclude that buildup of pre-cholesterol sterol intermediates interferes with midline fusion of facial structures in mice [1].
  • Sites of 5-HT immunoreactivity were found in a variety of locations in tissues of the head and neck, which are either epithelia derived from the non-neural ectoderm or are non-neuronal midline brain structures [28].
  • We concluded that the chondroitin sulfate moieties of the proteoglycans are involved in patterning the early phase of axonal growth across the midline and at a later stage controlling the axon divergence at the chiasm [29].
  • PGE precursors and their neuronal descendants are organised into two polyclonal groups of similar sizes that exhibit parasagittal patterning and generally respect the midline [30].

Physical interactions of Mid1

  • 125I-EGF binding sites were localized throughout the palate mesenchyme except in a region immediately adjacent to the midline seam [31].

Regulatory relationships of Mid1


Other interactions of Mid1

  • Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system [36].
  • Gli2 mutants fail to develop a floor plate yet still develop motor neurons, which occupy the ventral midline of the neural tube [37].
  • These results demonstrate that whereas Slit1 and Slit2 are not necessary for tangential migration of interneurons to the cortex, these proteins regulate neuronal migration within the basal telencephalon by controlling cell positioning close to the midline [38].
  • Morphological and gene expression data further indicate that a functional midline is not maintained along the whole prosomere 1 in Msx1 mutant mice [39].
  • The most probable cause for this left-right defect in Dll1 mutant embryos is a failure in the development of proper midline structures [40].

Analytical, diagnostic and therapeutic context of Mid1

  • METHODS: Adult male mice (C57BL/6, CRF(1)-deficient, and wild-type), fasted for 16-18 hours, were anesthetized for 10 minutes and had a midline celiotomy and cecal exteriorization and palpation for 30 or 60 seconds or no surgery (sham) [41].
  • Whole-mount in situ hybridization confirmed the dissection studies and demonstrated that Xwnt-4 transcripts are expressed in the dorsal midline of the midbrain, hindbrain and the floor plate of the neural tube [42].
  • Injection of DiI into the node, and electroporation of a GFP expression vector into the midline neural plate, revealed defective convergent extension in both axial mesoderm and neuroepithelium, before the onset of neurulation [43].
  • Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP approximately 35 mm Hg for 90 min), and resuscitation [44].
  • Using immunocytochemistry, we also show that at E13.5, 5-HT-positive neurons in the midline extend over a larger rostro-caudal distance than at E11.5, and that in the presumptive initiating zone, cell bodies occupy a band that extends 200 mum laterally on each side of the midline, with extensive axonal processes [45].


  1. Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin. Engelking, L.J., Evers, B.M., Richardson, J.A., Goldstein, J.L., Brown, M.S., Liang, G. J. Clin. Invest. (2006) [Pubmed]
  2. FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Beggs, H.E., Schahin-Reed, D., Zang, K., Goebbels, S., Nave, K.A., Gorski, J., Jones, K.R., Sretavan, D., Reichardt, L.F. Neuron (2003) [Pubmed]
  3. MARCKS deficiency in mice leads to abnormal brain development and perinatal death. Stumpo, D.J., Bock, C.B., Tuttle, J.S., Blackshear, P.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  4. A mutation of beta -actin that alters depolymerization dynamics is associated with autosomal dominant developmental malformations, deafness, and dystonia. Procaccio, V., Salazar, G., Ono, S., Styers, M.L., Gearing, M., Davila, A., Jimenez, R., Juncos, J., Gutekunst, C.A., Meroni, G., Fontanella, B., Sontag, E., Sontag, J.M., Faundez, V., Wainer, B.H. Am. J. Hum. Genet. (2006) [Pubmed]
  5. Trauma-hemorrhage induces depressed splenic dendritic cell functions in mice. Kawasaki, T., Hubbard, W.J., Choudhry, M.A., Schwacha, M.G., Bland, K.I., Chaudry, I.H. J. Immunol. (2006) [Pubmed]
  6. Guidance of retinal fibers in the optic chiasm. Godement, P., Mason, C.A. Perspectives on developmental neurobiology. (1993) [Pubmed]
  7. Magnitude of binocular vision controlled by islet-2 repression of a genetic program that specifies laterality of retinal axon pathfinding. Pak, W., Hindges, R., Lim, Y.S., Pfaff, S.L., O'Leary, D.D. Cell (2004) [Pubmed]
  8. Neuronal pathfinding is abnormal in mice lacking the neuronal growth cone protein GAP-43. Strittmatter, S.M., Fankhauser, C., Huang, P.L., Mashimo, H., Fishman, M.C. Cell (1995) [Pubmed]
  9. HNF-3 beta as a regulator of floor plate development. Sasaki, H., Hogan, B.L. Cell (1994) [Pubmed]
  10. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Urbánek, P., Wang, Z.Q., Fetka, I., Wagner, E.F., Busslinger, M. Cell (1994) [Pubmed]
  11. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Chiang, C., Litingtung, Y., Lee, E., Young, K.E., Corden, J.L., Westphal, H., Beachy, P.A. Nature (1996) [Pubmed]
  12. Differential Transcriptional Regulation by Mouse Single-minded 2s. Metz, R.P., Kwak, H.I., Gustafson, T., Laffin, B., Porter, W.W. J. Biol. Chem. (2006) [Pubmed]
  13. Hemorrhage decreases macrophage inflammatory protein 2 and interleukin-6 release: a possible mechanism for increased wound infection. Angele, M.K., Knöferl, M.W., Schwacha, M.G., Ayala, A., Bland, K.I., Cioffi, W.G., Josephson, S.L., Chaudry, I.H. Ann. Surg. (1999) [Pubmed]
  14. The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defects. Anthony, T.E., Heintz, N. J. Comp. Neurol. (2007) [Pubmed]
  15. Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol. Angele, M.K., Nitsch, S., Knoferl, M.W., Ayala, A., Angele, P., Schildberg, F.W., Jauch, K.W., Chaudry, I.H. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  16. Colon adenocarcinoma and B-16 melanoma grow larger following laparotomy vs. pneumoperitoneum in a murine model. Southall, J.C., Lee, S.W., Allendorf, J.D., Bessler, M., Whelan, R.L. Dis. Colon Rectum (1998) [Pubmed]
  17. The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region. Dal Zotto, L., Quaderi, N.A., Elliott, R., Lingerfelter, P.A., Carrel, L., Valsecchi, V., Montini, E., Yen, C.H., Chapman, V., Kalcheva, I., Arrigo, G., Zuffardi, O., Thomas, S., Willard, H.F., Ballabio, A., Disteche, C.M., Rugarli, E.I. Hum. Mol. Genet. (1998) [Pubmed]
  18. Cooperation of sonic hedgehog enhancers in midline expression. Ertzer, R., Müller, F., Hadzhiev, Y., Rathnam, S., Fischer, N., Rastegar, S., Strähle, U. Dev. Biol. (2007) [Pubmed]
  19. FXY2/MID2, a gene related to the X-linked Opitz syndrome gene FXY/MID1, maps to Xq22 and encodes a FNIII domain-containing protein that associates with microtubules. Perry, J., Short, K.M., Romer, J.T., Swift, S., Cox, T.C., Ashworth, A. Genomics (1999) [Pubmed]
  20. Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein. Wang, M.Z., Jin, P., Bumcrot, D.A., Marigo, V., McMahon, A.P., Wang, E.A., Woolf, T., Pang, K. Nat. Med. (1995) [Pubmed]
  21. Recombination explains isochores in mammalian genomes. Montoya-Burgos, J.I., Boursot, P., Galtier, N. Trends Genet. (2003) [Pubmed]
  22. Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Chen, L., Liao, G., Yang, L., Campbell, K., Nakafuku, M., Kuan, C.Y., Zheng, Y. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  23. Specification of optic nerve oligodendrocyte precursors by retinal ganglion cell axons. Gao, L., Miller, R.H. J. Neurosci. (2006) [Pubmed]
  24. Postnatally induced formation of the corpus callosum in acallosal mice on glia-coated cellulose bridges. Silver, J., Ogawa, M.Y. Science (1983) [Pubmed]
  25. Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Kullander, K., Croll, S.D., Zimmer, M., Pan, L., McClain, J., Hughes, V., Zabski, S., DeChiara, T.M., Klein, R., Yancopoulos, G.D., Gale, N.W. Genes Dev. (2001) [Pubmed]
  26. Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Vincent, S.D., Dunn, N.R., Hayashi, S., Norris, D.P., Robertson, E.J. Genes Dev. (2003) [Pubmed]
  27. Retinal axon pathfinding in the optic chiasm: divergence of crossed and uncrossed fibers. Godement, P., Salaün, J., Mason, C.A. Neuron (1990) [Pubmed]
  28. Serotonin and morphogenesis. I. Sites of serotonin uptake and -binding protein immunoreactivity in the midgestation mouse embryo. Lauder, J.M., Tamir, H., Sadler, T.W. Development (1988) [Pubmed]
  29. Axon routing at the optic chiasm after enzymatic removal of chondroitin sulfate in mouse embryos. Chung, K.Y., Taylor, J.S., Shum, D.K., Chan, S.O. Development (2000) [Pubmed]
  30. Retrospective clonal analysis of the cerebellum using genetic laacZ/lacZ mouse mosaics. Mathis, L., Bonnerot, C., Puelles, L., Nicolas, J.F. Development (1997) [Pubmed]
  31. The distribution of epidermal growth factor binding sites in the developing mouse palate. Brunet, C.L., Sharpe, P.M., Ferguson, M.W. Int. J. Dev. Biol. (1993) [Pubmed]
  32. Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Yamamoto, M., Mine, N., Mochida, K., Sakai, Y., Saijoh, Y., Meno, C., Hamada, H. Development (2003) [Pubmed]
  33. Zic4, a zinc-finger transcription factor, is expressed in the developing mouse nervous system. Gaston-Massuet, C., Henderson, D.J., Greene, N.D., Copp, A.J. Dev. Dyn. (2005) [Pubmed]
  34. Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. Shu, T., Butz, K.G., Plachez, C., Gronostajski, R.M., Richards, L.J. J. Neurosci. (2003) [Pubmed]
  35. Expression of Runx1, -2 and -3 during tooth, palate and craniofacial bone development. Yamashiro, T., Aberg, T., Levanon, D., Groner, Y., Thesleff, I. Gene Expr. Patterns (2002) [Pubmed]
  36. Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Plump, A.S., Erskine, L., Sabatier, C., Brose, K., Epstein, C.J., Goodman, C.S., Mason, C.A., Tessier-Lavigne, M. Neuron (2002) [Pubmed]
  37. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Ding, Q., Motoyama, J., Gasca, S., Mo, R., Sasaki, H., Rossant, J., Hui, C.C. Development (1998) [Pubmed]
  38. Directional guidance of interneuron migration to the cerebral cortex relies on subcortical Slit1/2-independent repulsion and cortical attraction. Marín, O., Plump, A.S., Flames, N., Sánchez-Camacho, C., Tessier-Lavigne, M., Rubenstein, J.L. Development (2003) [Pubmed]
  39. Msx1 is required for dorsal diencephalon patterning. Bach, A., Lallemand, Y., Nicola, M.A., Ramos, C., Mathis, L., Maufras, M., Robert, B. Development (2003) [Pubmed]
  40. Node and midline defects are associated with left-right development in Delta1 mutant embryos. Przemeck, G.K., Heinzmann, U., Beckers, J., Hrabé de Angelis, M. Development (2003) [Pubmed]
  41. Corticotropin-releasing factor receptor 1-deficient mice do not develop postoperative gastric ileus. Luckey, A., Wang, L., Jamieson, P.M., Basa, N.R., Million, M., Czimmer, J., Vale, W., Taché, Y. Gastroenterology (2003) [Pubmed]
  42. Analysis of Xwnt-4 in embryos of Xenopus laevis: a Wnt family member expressed in the brain and floor plate. McGrew, L.L., Otte, A.P., Moon, R.T. Development (1992) [Pubmed]
  43. Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Ybot-Gonzalez, P., Savery, D., Gerrelli, D., Signore, M., Mitchell, C.E., Faux, C.H., Greene, N.D., Copp, A.J. Development (2007) [Pubmed]
  44. The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage. Thobe, B.M., Frink, M., Hildebrand, F., Schwacha, M.G., Hubbard, W.J., Choudhry, M.A., Chaudry, I.H. J. Cell. Physiol. (2007) [Pubmed]
  45. Primary role of the serotonergic midline system in synchronized spontaneous activity during development of the embryonic mouse hindbrain. Hunt, P.N., Gust, J., McCabe, A.K., Bosma, M.M. J. Neurobiol. (2006) [Pubmed]
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