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JOURNAL ARTICLES
The Caenorhabditis elegans lim-6 LIM homeobox gene regulates neurite outgrowth and function of particular GABAergic neurons
O. Hobert, K. Tessmar, G. Ruvkun
Development 1999 126: 1547-1562;

Summary

We describe here the functional analysis of the C. elegans LIM homeobox gene lim-6, the ortholog of the mammalian Lmx-1a and b genes that regulate limb, CNS, kidney and eye development. lim-6 is expressed in a small number of sensory-, inter- and motorneurons, in epithelial cells of the uterus and in the excretory system. Loss of lim-6 function affects late events in the differentiation of two classes of GABAergic motorneurons which control rhythmic enteric muscle contraction. lim-6 is required to specify the correct axon morphology of these neurons and also regulates expression of glutamic acid decarboxylase, the rate limiting enzyme of GABA synthesis in these neurons. Moreover, lim-6 gene activity and GABA signaling regulate neuroendocrine outputs of the nervous system. In the chemosensory system lim-6 regulates the asymmetric expression of a probable chemosensory receptor. lim-6 is also required in epithelial cells for uterine morphogenesis. We compare the function of lim-6 to those of other LIM homeobox genes in C. elegans and suggest that LIM homeobox genes share the common theme of controlling terminal neural differentiation steps that when disrupted lead to specific neuroanatomical and neural function defects.

Reference

    1. Bargmann C. I.,
    2. Horvitz H. R.
    (1991) Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans. Neuron 7, 729–742
    OpenUrlCrossRefPubMedWeb of Science
    1. Bargmann C. I.,
    2. Kaplan J. M.
    (1998) Signal transduction in the Caenorhabditis elegans nervous system. Ann. Rev. Neurosci 21, 279–308
    OpenUrlCrossRefPubMedWeb of Science
    1. Basson M.,
    2. Horvitz H. R.
    (1996) The Caenorhabditis elegans gene sem-4 controls neuronal and mesodermal cell development and encodes a zinc finger protein. Genes Dev 10, 1953–1965
    OpenUrlAbstract/FREE Full Text
    1. Benveniste R. J.,
    2. Thor S.,
    3. Thomas J. B.,
    4. Taghert P. H.
    (1998) Cell type-specific regulation of the Drosophila FMRF-NH2 neuropeptide gene by Apterous, a LIM homeodomain transcription factor. Development 125, 4757–4765
    OpenUrlAbstract
    1. Bredt D. S.
    (1998) Sorting out genes that regulate epithelial and neuronal polarity. Cell 94, 691–4
    OpenUrlCrossRefPubMedWeb of Science
    1. Chen H.,
    2. Lun Y.,
    3. Ovchinnikov D.,
    4. Kokubo H.,
    5. Oberg K. C.,
    6. Pepicelli C. V.,
    7. Gan L.,
    8. Lee B.,
    9. Johnson R. L.
    (1998) Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat. Genet 19, 51–55
    OpenUrlCrossRefPubMedWeb of Science
    1. Chen H.,
    2. Ovchinnikov D.,
    3. Pressman C. L.,
    4. Aulehla A.,
    5. Lun Y.,
    6. Johnson R. L.
    (1998) Multiple calvarial defects in lmx1b mutant mice. Dev. Genet 22, 314–320
    OpenUrlCrossRefPubMed
    1. Coburn C. M.,
    2. Bargmann C. I.
    (1996) A putative cyclic nucleotide-gated channel is required for sensory development and function in C. elegans. Neuron 17, 695–706
    OpenUrlCrossRefPubMedWeb of Science
    1. Coburn C. M.,
    2. Mori I.,
    3. Ohshima Y.,
    4. Bargmann C. I.
    (1998) A cyclic nucleotide-gated channel inhibits sensory axon outgrowth in larval and adult Caenorhabditis elegans: a distinct pathway for maintenance of sensory axon structure. Development 125, 249–258
    OpenUrlAbstract
    1. Dahm L. M.,
    2. Landmesser L. T.
    (1988) The regulation of intramuscular nerve branching during normal development and following activity blockade. Dev. Biol 130, 621–644
    OpenUrlCrossRefPubMedWeb of Science
    1. Dahm L. M.,
    2. Landmesser L. T.
    (1991) The regulation of synaptogenesis during normal development and following activity blockade. J. Neurosci 11, 238–255
    OpenUrlAbstract
    1. Dawid I. B.,
    2. Breen J. J.,
    3. Toyama R.
    (1998) LIM domains: multiple roles as adapters and functional modifiers in protein interactions. Trends Genet 14, 156–162
    OpenUrlCrossRefPubMedWeb of Science
    1. Dreyer S. D.,
    2. Zhou G.,
    3. Baldini A.,
    4. Winterpacht A.,
    5. Zabel B.,
    6. Cole W.,
    7. Johnson R. L.,
    8. Lee B.
    (1998) Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat. Genet 19, 47–50
    OpenUrlCrossRefPubMedWeb of Science
    1. Duret L.,
    2. Guex N.,
    3. Peitsch M. C.,
    4. Bairoch A.
    (1998) New insulin-like proteins with atypical disulfide bond pattern characterized in Caenorhabditis elegans by comparative sequence analysis and homology modeling. Genome Res 8, 348–353
    OpenUrlAbstract/FREE Full Text
    1. Freyd G.,
    2. Kim S. K.,
    3. Horvitz H. R.
    (1990) Novel cysteine-rich motif and homeodomain in the product of the Caenorhabditis elegans cell lineage gene lin-11. Nature 344, 876–9
    OpenUrlCrossRefPubMedWeb of Science
    1. German M. S.,
    2. Wang J.,
    3. Chadwick R. B.,
    4. Rutter W. J.
    (1992) Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex. Genes Dev 6, 2165–2176
    OpenUrlAbstract/FREE Full Text
    1. Granato M.,
    2. Schnabel H.,
    3. Schnabel R.
    (1994) pha-1, a selectable marker for gene transfer in C. elegans. Nucleic Acids Res 22, 1762–3
    OpenUrlFREE Full Text
    1. Grider J. R.,
    2. Makhlouf G. M.
    (1992) Enteric GABA: mode of action and role in the regulation of the peristaltic reflex. Am. J. Physiol 262, 690–694
    OpenUrl
    1. Gu X. H.,
    2. Kurose T.,
    3. Kato S.,
    4. Masuda K.,
    5. Tsuda K.,
    6. Ishida H.,
    7. Seino Y.
    (1993) Suppressive effect of GABA on insulin secretion from the pancreatic beta-cells in the rat. Life Sci 52, 687–694
    OpenUrlCrossRefPubMedWeb of Science
    1. Hart A. C.,
    2. Sims S.,
    3. Kaplan J. M.
    (1995) Synaptic code for sensory modalities revealed by C. elegans GLR-1 glutamate receptor. Nature 378, 82–85
    OpenUrlCrossRefPubMedWeb of Science
    1. Hobert O.,
    2. D'Alberti T.,
    3. Liu Y.,
    4. Ruvkun G.
    (1998) Control of neural development and function in a thermoregulatory network by the LIM homeobox gene lin-11. J. Neurosci 18, 2084–2096
    OpenUrlAbstract/FREE Full Text
    1. Hobert O.,
    2. Mori I.,
    3. Yamashita Y.,
    4. Honda H.,
    5. Ohshima Y.,
    6. Liu Y.,
    7. Ruvkun G.
    (1997) Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene. Neuron 19, 3453–3457
    OpenUrl
    1. Iannotti C. A.,
    2. Inoue H.,
    3. Bernal E.,
    4. Aoki M.,
    5. Liu L.,
    6. Donis-Keller H.,
    7. German M. S.,
    8. Permutt M. A.
    (1997). Identification of a human LMX1 (LMX1.1)-related gene, LMX1.2: tissue-specific expression and linkage mapping on chromosome 9. Genomics 46, 520–524
    OpenUrlCrossRefPubMedWeb of Science
    1. Jansen G.,
    2. Hazendonk E.,
    3. Thijssen K. L.,
    4. Plasterk R. H.
    (1997) Reverse genetics by chemical mutagenesis in Caenorhabditis elegans. Nat. Genet 17, 119–121
    OpenUrlCrossRefPubMedWeb of Science
    1. Jessen K. R.,
    2. Hills J. M.,
    3. Saffrey M. J.
    (1986) Immunohistochemical demonstration of GABAergic neurons in the enteric nervous system. J. Neurosci 6, 1628–1634
    OpenUrlAbstract
    1. Jin Y.,
    2. Hoskins R.,
    3. Horvitz H. R.
    (1994) Control of type-D GABAergic neuron differentiation by C. elegans UNC-30 homeodomain protein. Nature 372, 780–783
    OpenUrlCrossRefPubMedWeb of Science
    1. Kimura K. D.,
    2. Tissenbaum H. A.,
    3. Liu Y.,
    4. Ruvkun G.
    (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans [see comments]. Science 277, 942–946
    OpenUrlAbstract/FREE Full Text
    1. Liu D. W.,
    2. Thomas J. H.
    (1994) Regulation of a periodic motor program in C. elegans. J. Neurosci 14, 1953–1962
    OpenUrlAbstract
    1. Lundgren S. E.,
    2. Callahan C. A.,
    3. Thor S.,
    4. Thomas J. B.
    (1995) Control of neuronal pathway selection by the Drosophila LIM homeodomain gene apterous. Development 121, 1769–1773
    OpenUrlAbstract
    1. Matise M. P.,
    2. Joyner A. L.
    (1997) Expression patterns of developmental control genes in normal and Engrailed-1 mutant mouse spinal cord reveal early diversity in developing interneurons. J. Neurosci 17, 7805–7816
    OpenUrlAbstract/FREE Full Text
    1. McIntire S.L.,
    2. Garriga G.,
    3. White J.,
    4. Jacobson D.,
    5. Horvitz H.R.
    (1992). Genes necessary for directed axonal elongation or fasciculation in C.elegans. Neuron 8, 307–322
    OpenUrlCrossRefPubMedWeb of Science
    1. McIntire S. L.,
    2. Jorgensen E.,
    3. Horvitz H. R.
    (1993) Genes required for GABA function in Caenorhabditis elegans [see comments]. Nature 364, 334–337
    OpenUrlCrossRefPubMedWeb of Science
    1. McIntire S. L.,
    2. Jorgensen E.,
    3. Kaplan J.,
    4. Horvitz H. R.
    (1993) The GABAergic nervous system of Caenorhabditis elegans [see comments]. Nature 364, 337–341
    OpenUrlCrossRefPubMedWeb of Science
    1. McIntire S. L.,
    2. Reimer R. J.,
    3. Schuske K.,
    4. Edwards R. H.,
    5. Jorgensen E. M.
    (1997) Identification and characterization of the vesicular GABA transporter. Nature 389, 870–876
    OpenUrlCrossRefPubMedWeb of Science
    1. Miller C.,
    2. Sassoon D. A.
    (1998) Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development 125, 3201–32311
    OpenUrlAbstract
    1. Miller D. M.,
    2. Shen M. M.,
    3. Shamu C. E.,
    4. Burglin T. R.,
    5. Ruvkun G.,
    6. Dubois M. L.,
    7. Ghee M.,
    8. Wilson L.
    (1992) C. elegans unc-4 gene encodes a homeodomain protein that determines the pattern of synaptic input to specific motor neurons. Nature 355, 841–845
    OpenUrlCrossRefPubMedWeb of Science
    1. Mori I.,
    2. Ohshima Y.
    (1995) Neural regulation of thermotaxis in Caenorhabditis elegans. Nature 376, 344–348
    OpenUrlCrossRefPubMedWeb of Science
    1. Nelson F. K.,
    2. Albert P. S.,
    3. Riddle D. L.
    (1983) Fine structure of the Caenorhabditis elegans secretory-excretory system. J. Ultrastruct. Res 82, 156–171
    OpenUrlCrossRefPubMedWeb of Science
    1. Nelson F. K.,
    2. Riddle D. L.
    (1984) Functional study of the Caenorhabditis elegans secretory-excretory system using laser microsurgery. J. Exp. Zool 231, 45–56
    OpenUrlCrossRefPubMedWeb of Science
    1. Newman A. P.,
    2. White J. G.,
    3. Sternberg P. W.
    (1996) Morphogenesis of the C. elegans hermaphrodite uterus. Development 122, 3617–3626
    OpenUrlAbstract
    1. Ogg S.,
    2. Paradis S.,
    3. Gottlieb S.,
    4. Patterson G. I.,
    5. Lee L.,
    6. Tissenbaum H. A.,
    7. Ruvkun G.
    (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999
    OpenUrlCrossRefPubMedWeb of Science
    1. Pfaff S. L.,
    2. Mendelsohn M.,
    3. Stewart C. L.,
    4. Edlund T.,
    5. Jessell T. M.
    (1996) Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84, 309–320
    OpenUrlCrossRefPubMedWeb of Science
    1. Porter F. D.,
    2. Drago J.,
    3. Xu Y.,
    4. Cheema S. S.,
    5. Wassif C.,
    6. Huang S. P.,
    7. Lee E.,
    8. Grinberg A.,
    9. Massalas J. S.,
    10. Bodine D.,
    11. Alt F.,
    12. Westphal H.
    (1997) Lhx2, a LIM homeobox gene, is required for eye, forebrain, and definitive erythrocyte development. Development 124, 2935–2944
    OpenUrlAbstract
    1. Ren P.,
    2. Lim C. S.,
    3. Johnsen R.,
    4. Albert P. S.,
    5. Pilgrim D.,
    6. Riddle D. L.
    (1996) Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 274, 1389–1391
    OpenUrlAbstract/FREE Full Text
    1. Riddle R. D.,
    2. Ensini M.,
    3. Nelson C.,
    4. Tsuchida T.,
    5. Jessell T. M.,
    6. Tabin C.
    (1995) Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb. Cell 83, 631–640
    OpenUrlCrossRefPubMedWeb of Science
    1. Rongo C.,
    2. Whitfield C. W.,
    3. Rodal A.,
    4. Kim S. K.,
    5. Kaplan J. M.
    (1998) LIN-10 is a shared component of the polarized protein localization pathways in neurons and epithelia. Cell 94, 751–759
    OpenUrlCrossRefPubMedWeb of Science
    1. Ruvkun G.,
    2. Hobert O.
    (1998) The Taxonomy of Developmental Control in Caenorhabditis elegans. Science 282, 2033–2041
    OpenUrlAbstract/FREE Full Text
    1. Sanders K. M.
    (1996) A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 111, 492–515
    OpenUrlCrossRefPubMedWeb of Science
    1. Sawa H.,
    2. Lobel L.,
    3. Horvitz H. R.
    (1996) The Caenorhabditis elegans gene lin-17, which is required for certain asymmetric cell divisions, encodes a putative seven-transmembrane protein similar to the Drosophila frizzled protein. Genes Dev 10, 2189–2197
    OpenUrlAbstract/FREE Full Text
    1. Schinkmann K.,
    2. Li C.
    (1992) Localization of FMRFamide-like peptides in Caenorhabditis elegans. J. Comp. Neurol 316, 251–260
    OpenUrlCrossRefPubMedWeb of Science
    1. Sharma K.,
    2. Sheng H. Z.,
    3. Lettieri K.,
    4. Li H.,
    5. Karavanov A.,
    6. Potter S.,
    7. Westphal H.,
    8. Pfaff S. L.
    (1998) LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons. Cell 95, 817–828
    OpenUrlCrossRefPubMedWeb of Science
    1. Shatz C. J.,
    2. Stryker M. P.
    (1988) Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents. Science 242, 87–89
    OpenUrlAbstract/FREE Full Text
    1. Sorenson R. L.,
    2. Garry D. G.,
    3. Brelje T. C.
    (1991) Structural and functional considerations of GABA in islets of Langerhans, beta-cells and nerves. Diabetes 40, 1365–1374
    OpenUrlAbstract/FREE Full Text
    1. Sulston J. E.
    (1983) Neuronal cell lineages in the nematode Caenorhabditis elegans. ColdSpring Harb. Symp. Quant. Biol 48, 443–452
    OpenUrlAbstract/FREE Full Text
    1. Thomas J. H.
    (1990) Genetic analysis of defecation in Caenorhabditis elegans. Genetics 124, 855–872
    OpenUrlAbstract/FREE Full Text
    1. Thor S.,
    2. Thomas J. B.
    (1997) The Drosophila islet gene governs axon pathfinding and neurotransmitter identity. Neuron 18, 397–409
    OpenUrlCrossRefPubMedWeb of Science
    1. Thor S.,
    2. Andersson S.G.E.,
    3. Tomlinson A.,
    4. Thomas J.B.
    (1999) A LIM-homeodomain combinatorial code for motor neuron pathway selection. Nature 397, 76–80
    OpenUrlCrossRefPubMedWeb of Science
    1. Tsuchida T.,
    2. Ensini M.,
    3. Morton S. B.,
    4. Baldassare M.,
    5. Edlund T.,
    6. Jessell T. M.,
    7. Pfaff S. L.
    (1994) Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes [see comments]. Cell 79, 957–970
    OpenUrlCrossRefPubMedWeb of Science
    1. Vogel A.,
    2. Rodriguez C.,
    3. Warnken W.,
    4. Izpisua Belmonte J. C.
    (1995) Dorsal cell fate specified by chick Lmx1 during vertebrate limb development [published erratum appears in Nature 1996 Feb 29;379(6568):848]. Nature 378, 716–720
    OpenUrlCrossRefPubMedWeb of Science
    1. Wadsworth W. G.,
    2. Bhatt H.,
    3. Hedgecock E. M.
    (1996) Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans. Neuron 16, 35–46
    OpenUrlCrossRefPubMedWeb of Science
    1. Way J. C.,
    2. Chalfie M.
    (1989) The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types. Genes Dev 3, 1823–33
    OpenUrlAbstract/FREE Full Text
    1. Way J. C.,
    2. Chalfie M.
    (1988) mec-3, a homeobox-containing gene that specifies differentiation of the touch receptor neurons in C. elegans. Cell 54, 5–16
    OpenUrlCrossRefPubMedWeb of Science
    1. White J. G.,
    2. Southgate E.,
    3. Thomson J. N.
    (1992) Mutations in the Caenorhabditis elegans unc-4 gene alter the synaptic input to ventral cord motor neurons. Nature 355, 838–41
    OpenUrlCrossRefPubMedWeb of Science
    1. White J. G.,
    2. Southgate E.,
    3. Thomson J. N.,
    4. Brenner S.
    (1986) The structure of the nervous system of the nematode Caenorhabditis elegans. Phil. Trans. Royal Soc. London B 314, 1–340
    OpenUrlCrossRef
    1. Yu S.,
    2. Avery L.,
    3. Baude E.,
    4. Garbers D. L.
    (1997) Guanylyl cyclase expression in specific sensory neurons: a new family of chemosensory receptors. Proc. Natl. Acad. Sci. USA 94, 3384–7
    OpenUrlAbstract/FREE Full Text
    1. Zhou H. M.,
    2. Walthall W. W.
    (1998) UNC-55, an orphan nuclearhormone receptor, orchestrates synaptic specificity among two classes of motor neurons in Caenorhabditis elegans. J. Neurosci 18, 10438–10444
    OpenUrlAbstract/FREE Full Text
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JOURNAL ARTICLES
The Caenorhabditis elegans lim-6 LIM homeobox gene regulates neurite outgrowth and function of particular GABAergic neurons
O. Hobert, K. Tessmar, G. Ruvkun
Development 1999 126: 1547-1562;
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