Skip to main content
Log in

Transcriptional regulation of guidance at the midline and in motor circuits

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Axon navigation through the developing body of an embryo is a challenging and exquisitely precise process. Axonal processes within the nervous system harbor extremely complicated internal regulatory mechanisms that enable each of them to respond to environmental cues in a unique way, so that every single neuron has an exact stereotypical localization and axonal projection pattern. Receptors and adhesion molecules expressed on axonal membranes will determine their guidance properties. Axon guidance is thought to be controlled to a large extent through transcription factor codes. These codes would be responsible for the deployment of specific guidance receptors and adhesion molecules on axonal membranes to allow them to reach their targets. Although families of transcriptional regulators as well as families of guidance molecules have been conserved across evolution, their relationships seem to have developed independently. This review focuses on the midline and the neuromuscular system in both vertebrates and Drosophila in which such relationships have been particularly well studied.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Dickson BJ, Zou Y (2010) Navigating intermediate targets: the nervous system midline. Cold Spring Harb Perspect Biol 2:a002055

    PubMed  Google Scholar 

  2. Nawabi H, Castellani V (2011) Axonal commissures in the central nervous system: how to cross the midline? Cell Mol Life Sci 68(15):2539–2553

    CAS  PubMed  Google Scholar 

  3. Kennedy TE, Serafini T, de la Torre JR, Tessier-Lavigne M (1994) Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78(3):425–435

    CAS  PubMed  Google Scholar 

  4. Charron F, Stein E, Jeong J, McMahon AP, Tessier-Lavigne M (2003) The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 113(1):11–23

    CAS  PubMed  Google Scholar 

  5. Ruiz de Almodovar C, Fabre PJ, Knevels E, Coulon C, Segura I, Haddick PC, Aerts L, Delattin N, Strasser G, Oh WJ, Lange C, Vinckier S, Haigh J, Fouquet C, Gu C, Alitalo K, Castellani V, Tessier-Lavigne M, Chedotal A, Charron F, Carmeliet P (2011) VEGF mediates commissural axon chemoattraction through its receptor Flk1. Neuron 70(5):966–978

    CAS  PubMed  Google Scholar 

  6. Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, Tessier-Lavigne M, Kidd T (1999) Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96(6):795–806

    CAS  PubMed  Google Scholar 

  7. Long H, Sabatier C, Ma L, Plump A, Yuan W, Ornitz DM, Tamada A, Murakami F, Goodman CS, Tessier-Lavigne M (2004) Conserved roles for Slit and Robo proteins in midline commissural axon guidance. Neuron 42(2):213–223

    CAS  PubMed  Google Scholar 

  8. Shirasaki R, Katsumata R, Murakami F (1998) Change in chemoattractant responsiveness of developing axons at an intermediate target. Science 279(5347):105–107

    CAS  PubMed  Google Scholar 

  9. Chen Z, Gore BB, Long H, Ma L, Tessier-Lavigne M (2008) Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion. Neuron 58(3):325–332

    CAS  PubMed  Google Scholar 

  10. Nawabi H, Briancon-Marjollet A, Clark C, Sanyas I, Takamatsu H, Okuno T, Kumanogoh A, Bozon M, Takeshima K, Yoshida Y, Moret F, Abouzid K, Castellani V (2010) A midline switch of receptor processing regulates commissural axon guidance in vertebrates. Genes Dev 24(4):396–410

    CAS  PubMed  Google Scholar 

  11. Bourikas D, Pekarik V, Baeriswyl T, Grunditz A, Sadhu R, Nardo M, Stoeckli ET (2005) Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord. Nat Neurosci 8(3):297–304

    CAS  PubMed  Google Scholar 

  12. Yam PT, Kent CB, Morin S, Farmer WT, Alchini R, Lepelletier L, Colman DR, Tessier-Lavigne M, Fournier AE, Charron F (2012) 14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing. Neuron 76(4):735–749

    CAS  PubMed  Google Scholar 

  13. Keino-Masu K, Masu M, Hinck L, Leonardo ED, Chan SS, Culotti JG, Tessier-Lavigne M (1996) Deleted in colorectal cancer (DCC) encodes a netrin receptor. Cell 87:175–185

    CAS  PubMed  Google Scholar 

  14. Okada A, Charron F, Morin S, Shin DS, Wong K, Fabre PJ, Tessier-Lavigne M, Mcconnell SK (2006) Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444(7117):369–373

    CAS  PubMed  Google Scholar 

  15. Zou Y, Stoeckli E, Chen H, Tessier-Lavigne M (2000) Squeezing axons out of the gray matter: a role for slit and semaphorin proteins from midline and ventral spinal cord. Cell 102(3):363–375

    CAS  PubMed  Google Scholar 

  16. Camurri L, Mambetisaeva E, Sundaresan V (2004) Rig-1 a new member of Robo family genes exhibits distinct pattern of expression during mouse development. Gene Expr Patterns 4:99–103

    CAS  PubMed  Google Scholar 

  17. Sundaresan V, Mambetisaeva E, Andrews W, Annan A, Knöll B, Tear G, Bannister L (2004) Dynamic expression patterns of Robo (Robo1 and Robo2) in the developing murine central nervous system. J Comp Neurol 468:467–481

    CAS  PubMed  Google Scholar 

  18. Sabatier C, Plump AS, Ma L, Brose K, Tamada A, Murakami F, Lee EY-HP, Tessier-Lavigne M (2004) The divergent Robo family protein rig-1/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell 117:157–169

    CAS  PubMed  Google Scholar 

  19. Tessier-Lavigne M, Placzek M, Lumsden AG, Dodd J, Jessell TM (1988) Chemotropic guidance of developing axons in the mammalian central nervous system. Nature 336(6201):775–778

    CAS  PubMed  Google Scholar 

  20. Placzek M, Tessier-Lavigne M, Yamada T, Jessell T, Dodd J (1990) Mesodermal control of neural cell identity: floor plate induction by the notochord. Science 250(4983):985–988

    CAS  PubMed  Google Scholar 

  21. Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R, Skarnes WC, Tessier-Lavigne M (1996) Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87:1001–1014

    CAS  PubMed  Google Scholar 

  22. Lauderdale JD, Davis NM, Kuwada JY (1997) Axon tracts correlate with netrin-1a expression in the zebrafish embryo. Mol Cell Neurosci 9:293–313

    CAS  PubMed  Google Scholar 

  23. Strähle U, Fischer N, Blader P (1997) Expression and regulation of a netrin homologue in the zebrafish embryo. Mech Dev 62:147–160

    PubMed  Google Scholar 

  24. Hammerschmidt M, Bitgood MJ, McMahon AP (1996) Protein kinase A is a common negative regulator of Hedgehog signaling in the vertebrate embryo. Genes Dev 10:647–658

    CAS  PubMed  Google Scholar 

  25. Rastegar S, Albert S, Le Roux I, Fischer N, Blader P, Müller F, Strähle U (2002) A floor plate enhancer of the zebrafish netrin1 gene requires Cyclops (Nodal) signalling and the winged helix transcription factor FoxA2. Dev Biol 252(1):1–14

    CAS  PubMed  Google Scholar 

  26. Jeong Y, Epstein DJ (2003) Distinct regulators of Shh transcription in the floor plate and notochord indicate separate origins for these tissues in the mouse node. Development 130(16):3891–3902

    CAS  PubMed  Google Scholar 

  27. Metzakopian E, Lin W, Salmon-Divon M, Dvinge H, Andersson E, Ericson J, Perlmann T, Whitsett JA, Bertone P, Ang S-L (2012) Genome-wide characterization of Foxa2 targets reveals upregulation of floor plate genes and repression of ventrolateral genes in midbrain dopaminergic progenitors. Development 139(14):2625–2634

    CAS  PubMed  Google Scholar 

  28. Caspary T, Anderson KV (2003) Patterning cell types in the dorsal spinal cord: what the mouse mutants say. Nat Rev Neurosci 4:289–297

    PubMed  Google Scholar 

  29. Helms AW, Johnson JE (2003) Specification of dorsal spinal cord interneurons. Curr Opin Neurobiol 13:42–49

    CAS  PubMed  Google Scholar 

  30. Gross MK, Dottori M, Goulding M (2002) Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34:535–549

    CAS  PubMed  Google Scholar 

  31. Müller T, Brohmann H, Pierani A, Heppenstall PA, Lewin GR, Jessell TM, Birchmeier C (2002) The homeodomain factor lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron 34:551–562

    PubMed  Google Scholar 

  32. Qian Y, Shirasawa S, Chen C-L, Cheng L, Ma Q (2002) Proper development of relay somatic sensory neurons and D2/D4 interneurons requires homeobox genes Rnx/Tlx-3 and Tlx-1. Genes Dev 16:1220–1233

    CAS  PubMed  Google Scholar 

  33. Saba R, Nakatsuji N, Saito T (2003) Mammalian BarH1 confers commissural neuron identity on dorsal cells in the spinal cord. J Neurosci 23:1987–1991

    CAS  PubMed  Google Scholar 

  34. Avraham O, Hadas Y, Vald L, Zisman S, Schejter A, Visel A, Klar A (2009) Transcriptional control of axonal guidance and sorting in dorsal interneurons by the Lim-HD proteins Lhx9 and Lhx1. Neural Dev 4:21

    PubMed Central  PubMed  Google Scholar 

  35. Avraham O, Hadas Y, Vald L, Hong S, Song M-R, Klar A (2010) Motor and dorsal root ganglion axons serve as choice points for the ipsilateral turning of dI3 axons. J Neurosci 30(46):15546–15557

    CAS  PubMed  Google Scholar 

  36. Bermingham NA, Hassan BA, Wang VY, Fernandez M, Banfi S, Bellen HJ, Fritzsch B, Zoghbi HY (2001) Proprioceptor pathway development is dependent on Math1. Neuron 30:411–422

    CAS  PubMed  Google Scholar 

  37. Gowan K, Helms AW, Hunsaker TL, Collisson T, Ebert PJ, Odom R, Johnson JE (2001) Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31:219–232

    CAS  PubMed  Google Scholar 

  38. Wilson SI, Shafer B, Lee KJ, Dodd J (2008) A molecular program for contralateral trajectory: Rig-1 control by LIM homeodomain transcription factors. Neuron 59:413–424

    CAS  PubMed  Google Scholar 

  39. Saba R, Johnson JE, Saito T (2005) Commissural neuron identity is specified by a homeodomain protein, Mbh1, that is directly downstream of Math1. Development 132:2147–2155

    CAS  PubMed  Google Scholar 

  40. Kawauchi D, Muroyama Y, Sato T, Saito T (2010) Expression of major guidance receptors is differentially regulated in spinal commissural neurons transfated by mammalian Barh genes. Dev Biol 344:1026–1034

    CAS  PubMed  Google Scholar 

  41. Marion J-F, Yang C, Caqueret A, Boucher F, Michaud JL (2005) Sim1 and Sim2 are required for the correct targeting of mammillary body axons. Development 132(24):5527–5537

    CAS  PubMed  Google Scholar 

  42. Schweitzer J, Löhr H, Bonkowsky JL, Hübscher K, Driever W (2013) Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism. Development 140(1):93–106

    CAS  PubMed  Google Scholar 

  43. Kolodziej PA, Timpe LC, Mitchell KJ, Fried SR, Goodman CS, Jan LY, Jan YN (1996) frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Cell 87:197–204

    CAS  PubMed  Google Scholar 

  44. Mitchell KJ, Doyle JL, Serafini T, Kennedy TE, Tessier-Lavigne M, Goodman CS, Dickson BJ (1996) Genetic analysis of Netrin genes in Drosophila: Netrins guide CNS commissural axons and peripheral motor axons. Neuron 17:203–215

    CAS  PubMed  Google Scholar 

  45. Harris R, Sabatelli LM, Seeger MA (1996) Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs. Neuron 17(2):217–228

    CAS  PubMed  Google Scholar 

  46. Kidd T, Brose K, Mitchell KJ, Fetter RD, Tessier-Lavigne M, Goodman CS, Tear G (1998) Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92:205–215

    CAS  PubMed  Google Scholar 

  47. Simpson JH, Bland KS, Fetter RD, Goodman CS (2000) Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position. Cell 103:1019–1032

    CAS  PubMed  Google Scholar 

  48. Rajagopalan S, Vivancos V, Nicolas E, Dickson BJ (2000) Selecting a longitudinal pathway: Robo receptors specify the lateral position of axons in the Drosophila CNS. Cell 103:1033–1045

    CAS  PubMed  Google Scholar 

  49. Spitzweck B, Brankatschk M, Dickson BJ (2010) Distinct protein domains and expression patterns confer divergent axon guidance functions for Drosophila Robo receptors. Cell 140:409–420

    CAS  PubMed  Google Scholar 

  50. Evans TA, Bashaw GJ (2010) Functional diversity of robo receptor immunoglobulin domains promotes distinct axon guidance decisions. Curr Biol 20(6):567–572

    CAS  PubMed  Google Scholar 

  51. Seeger M, Tear G, Ferres-Marco D, Goodman CS (1993) Mutations affecting growth cone guidance in Drosophila: genes necessary for guidance toward or away from the midline. Neuron 10:409–426

    CAS  PubMed  Google Scholar 

  52. Keleman K, Rajagopalan S, Cleppien D, Teis D, Paiha K, Huber LA, Technau GM, Dickson BJ (2002) Comm sorts robo to control axon guidance at the Drosophila midline. Cell 110:415–427

    CAS  PubMed  Google Scholar 

  53. Keleman K, Ribeiro C, Dickson BJ (2005) Comm function in commissural axon guidance: cell-autonomous sorting of Robo in vivo. Nat Neurosci 8:156–163

    CAS  PubMed  Google Scholar 

  54. Yang L, Garbe DS, Bashaw GJ (2009) A frazzled/DCC-dependent transcriptional switch regulates midline axon guidance. Science 324(5929):944–947

    CAS  PubMed  Google Scholar 

  55. Solano PJ, Mugat B, Martin D, Girard F, Huibant J-M, Ferraz C, Jacq B, Demaille J, Maschat F (2003) Genome-wide identification of in vivo Drosophila Engrailed-binding DNA fragments and related target genes. Development 130(7):1243–1254

    CAS  PubMed  Google Scholar 

  56. Joly W, Mugat B, Maschat F (2007) Engrailed controls the organization of the ventral nerve cord through frazzled regulation. Dev Biol 301:542–554

    CAS  PubMed  Google Scholar 

  57. Colomb S, Joly W, Bonneaud N, Maschat F (2008) A concerted action of Engrailed and Gooseberry-neuro in neuroblast 6-4 is triggering the formation of embryonic posterior commissure bundles. PLoS ONE 3:e2197

    PubMed Central  PubMed  Google Scholar 

  58. Liu Q-X, Hiramoto M, Ueda H, Gojobori T, Hiromi Y, Hirose S (2009) Midline governs axon pathfinding by coordinating expression of two major guidance systems. Genes Dev 23(10):1165–1170

    CAS  PubMed  Google Scholar 

  59. Crowner D, Madden K, Goeke S, Giniger E (2002) Lola regulates midline crossing of CNS axons in Drosophila. Development 129(6):1317–1325

    CAS  PubMed  Google Scholar 

  60. Dräger UC (1985) Birth dates of retinal ganglion cells giving rise to the crossed and uncrossed optic projections in the mouse. Proc R Soc Lond B 224:57–77

    PubMed  Google Scholar 

  61. Guillery RW, Mason CA, Taylor JS (1995) Developmental determinants at the mammalian optic chiasm. J Neurosci 15:4727–4737

    CAS  PubMed  Google Scholar 

  62. Petros TJ, Rebsam A, Mason CA (2008) Retinal axon growth at the optic chiasm: to cross or not to cross. Annu Rev Neurosci 31:295–315

    CAS  PubMed  Google Scholar 

  63. Nakagawa S, Brennan C, Johnson KG, Shewan D, Harris WA, Holt CE (2000) Ephrin-B regulates the Ipsilateral routing of retinal axons at the optic chiasm. Neuron 25:599–610

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Williams SE, Mann F, Erskine L, Sakurai T, Wei S, Rossi DJ, Gale NW, Holt CE, Mason CA, Henkemeyer M (2003) Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron 39:919–935

    CAS  PubMed  Google Scholar 

  65. García-Frigola C, Carreres MI, Vegar C, Mason C, Herrera E (2008) Zic2 promotes axonal divergence at the optic chiasm midline by EphB1-dependent and -independent mechanisms. Development 135(10):1833–1841

    PubMed  Google Scholar 

  66. Lee R, Petros TJ, Mason CA (2008) Zic2 regulates retinal ganglion cell axon avoidance of ephrinB2 through inducing expression of the guidance receptor EphB1. J Neurosci 28(23):5910–5919

    CAS  PubMed  Google Scholar 

  67. Petros TJ, Shrestha BR, Mason C (2009) Specificity and sufficiency of EphB1 in driving the ipsilateral retinal projection. J Neurosci 29:3463–3474

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Herrera E, Brown L, Aruga J, Rachel RA, Dolen G, Mikoshiba K, Brown S, Mason CA (2003) Zic2 patterns binocular vision by specifying the uncrossed retinal projection. Cell 114:545–557

    CAS  PubMed  Google Scholar 

  69. Pak W, Hindges R, Lim Y-S, Pfaff SL, O’Leary DDM (2004) Magnitude of binocular vision controlled by islet-2 repression of a genetic program that specifies laterality of retinal axon pathfinding. Cell 119:567–578

    CAS  PubMed  Google Scholar 

  70. Kuwajima T, Yoshida Y, Takegahara N, Petros TJ, Kumanogoh A, Jessell TM, Sakurai T, Mason C (2012) Optic chiasm presentation of Semaphorin6D in the context of Plexin-A1 and Nr-CAM promotes retinal axon midline crossing. Neuron 74(4):676–690

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Erskine L, Herrera E (2007) The retinal ganglion cell axon’s journey: insights into molecular mechanisms of axon guidance. Dev Biol 308(1):1–14

    CAS  PubMed  Google Scholar 

  72. Polleux F, Ince-Dunn G, Ghosh A (2007) Transcriptional regulation of vertebrate axon guidance and synapse formation. Nat Rev Neurosci 8:331–340

    CAS  PubMed  Google Scholar 

  73. Butler SJ, Tear G (2007) Getting axons onto the right path: the role of transcription factors in axon guidance. Development 134:439–448

    CAS  PubMed  Google Scholar 

  74. Bonanomi D, Pfaff SL (2010) Motor axon pathfinding. Cold Spring Harb Perspect Biol 2:a001735

    PubMed  Google Scholar 

  75. Dasen JS, Jessell TM (2009) Hox networks and the origins of motor neuron diversity. Curr Opin Genet Dev 88:169–200

    CAS  Google Scholar 

  76. Kania A, Jessell TM (2003) Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A: EphA interactions. Neuron 38:581–596

    CAS  PubMed  Google Scholar 

  77. Ryan JM, Cushman J, Jordan B, Samuels A, Frazer H, Baier C (1998) Topographic position of forelimb motoneuron pools is conserved in vertebrate evolution. Brain Behav Evol 51:90–99

    CAS  PubMed  Google Scholar 

  78. Landgraf M, Thor S (2006) Development of Drosophila motoneurons: specification and morphology. Semin Cell Dev Biol 17:3–11

    CAS  PubMed  Google Scholar 

  79. Layden MJ, Odden JP, Schmid A, Garces A, Thor S, Doe CQ (2006) Zfh1, a somatic motor neuron transcription factor, regulates axon exit from the CNS. Dev Biol 291:253–263

    CAS  PubMed  Google Scholar 

  80. Odden JP, Holbrook S, Doe CQ (2002) Drosophila HB9 is expressed in a subset of motoneurons and interneurons, where it regulates gene expression and axon pathfinding. J Neurosci 22:9143–9149

    CAS  PubMed  Google Scholar 

  81. Broihier HT, Kuzin A, Zhu Y, Odenwald W, Skeath JB (2004) Drosophila homeodomain protein Nkx6 coordinates motoneuron subtype identity and axonogenesis. Development 131:5233–5242

    CAS  PubMed  Google Scholar 

  82. Broihier HT, Skeath JB (2002) Drosophila homeodomain protein dHb9 directs neuronal fate via cross repressive and cell-nonautonomous mechanisms. Neuron 35:39–50

    CAS  PubMed  Google Scholar 

  83. Fujioka M, Lear BC, Landgraf M, Yusibova GL, Zhou J, Riley KM, Patel NH, Jaynes JB (2003) Even-skipped, acting as a repressor, regulates axonal projections in Drosophila. Development 130:5385–5400

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Landgraf M, Roy S, Prokop A, VijayRaghavan K, Bate M (1999) Even-skipped determines the dorsal growth of motor axons in Drosophila. Neuron 22:43–52

    CAS  PubMed  Google Scholar 

  85. Doe CQ, Smouse D, Goodman CS (1988) Control of neuronal fate by the Drosophila segmentation gene even-skipped. Nature 333:376–378

    CAS  PubMed  Google Scholar 

  86. Muhr J, Andersson E, Persson M, Jessell TM, Ericson J (2001) Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell 104:861–873

    CAS  PubMed  Google Scholar 

  87. Uhler J, Garbern J, Yang L, Kamholz J, Mellerick DM (2002) Nk6, a novel Drosophila homeobox gene regulated by vnd. Mech Dev 116:105–116

    CAS  PubMed  Google Scholar 

  88. Thor S, Andersson SGE, Tomlinson A, Thomas JB (1999) A LIM-homeodomain combinatorial code for motor-neuron pathway selection. Nature 397:76–80

    CAS  PubMed  Google Scholar 

  89. Fambrough D, Goodman CS (1996) The Drosophila beaten path gene encodes a novel secreted protein that regulates defasciculation at motor axon choice points. Cell 87:1049–1058

    CAS  PubMed  Google Scholar 

  90. Garces A, Thor S (2006) Specification of Drosophila aCC motoneuron identity by a genetic cascade involving even-skipped, grain and zfh1. Development 133:1445–1455

    CAS  PubMed  Google Scholar 

  91. Labrador JP, O’keefe D, Yoshikawa S, McKinnon RD, Thomas JB, Bashaw GJ (2005) The homeobox transcription factor even-skipped regulates netrin-receptor expression to control dorsal motor-axon projections in Drosophila. Curr Biol 15:1413–1419

    CAS  PubMed  Google Scholar 

  92. Keleman K, Dickson BJ (2001) Short- and long-range repulsion by the Drosophila Unc5 netrin receptor. Neuron 32:605–617

    CAS  PubMed  Google Scholar 

  93. Zarin AA, Daly AC, Hülsmeier J, Asadzadeh J, Labrador J-P (2012) A GATA/homeodomain transcriptional code regulates axon guidance through the Unc-5 receptor. Development 139:1798–1805

    CAS  PubMed  Google Scholar 

  94. Shishido E (1998) Drosophila synapse formation: regulation by transmembrane protein with Leu-rich repeats, CAPRICIOUS. Science 280:2118–2121

    CAS  PubMed  Google Scholar 

  95. Taniguchi H, Shishido E, Takeichi M, Nose A (2000) Functional dissection of drosophila capricious: its novel roles in neuronal pathfinding and selective synapse formation. J Neurobiol 42:104–116

    CAS  PubMed  Google Scholar 

  96. Inaki M, Yoshikawa S, Thomas JB, Aburatani H, Nose A (2007) Wnt4 is a local repulsive cue that determines synaptic target specificity. Curr Biol 17:1574–1579

    CAS  PubMed  Google Scholar 

  97. Inaki M, Shinza-kameda M, Ismat A, Frasch M, Nose A (2010) Drosophila Tey represses transcription of the repulsive cue Toll and generates neuromuscular target specificity. Development 2146:2139–2146

    Google Scholar 

  98. Rose D, Zhu X, Kose H, Hoang B, Cho J, Chiba A (1997) Toll, a muscle cell surface molecule, locally inhibits synaptic initiation of the RP3 motoneuron growth cone in Drosophila. Development 124:1561–1571

    CAS  PubMed  Google Scholar 

  99. Tixier V, Bataillé L, Jagla K (2010) Diversification of muscle types: recent insights from Drosophila. Exp Cell Res 316:3019–3027

    CAS  PubMed  Google Scholar 

  100. Nose A (2012) Generation of neuromuscular specificity in Drosophila: novel mechanisms revealed by new technologies. Front Mol Neurosci 5:1–11

    Google Scholar 

  101. Shirasaki R, Pfaff SL (2002) Transcriptional codes and the control of neuronal identity. Annu Rev Neurosci 25:251–281

    CAS  PubMed  Google Scholar 

  102. Jessell TM (2000) Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat Rev Genet 1:20–29

    CAS  PubMed  Google Scholar 

  103. Dessaud E, McMahon AP, Briscoe J (2008) Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development 135:2489–2503

    CAS  PubMed  Google Scholar 

  104. Arber S, Han B, Mendelsohn M, Smith M, Jessell TM, Sockanathan S (1999) Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron 23:659–674

    CAS  PubMed  Google Scholar 

  105. Thaler J, Harrison K, Sharma K, Lettieri K, Kehrl J, Pfaff SL (1999) Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron 23:675–687

    CAS  PubMed  Google Scholar 

  106. Pfaff SL, Mendelsohn M, Stewart CL, Edlund T, Jessell TM (1996) Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84:309–320

    CAS  PubMed  Google Scholar 

  107. Thaler JP, Koo SJ, Kania A, Lettieri K, Andrews S, Cox C, Jessell TM, Pfaff SL (2004) A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron 41:337–350

    CAS  PubMed  Google Scholar 

  108. Sharma K, Sheng HZ, Lettieri K, Li H, Karavanov A, Potter S, Westphal H, Pfaff SL (1998) LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons. Cell 95:817–828

    CAS  PubMed  Google Scholar 

  109. Philippidou P, Walsh CM, Aubin J, Jeannotte L, Dasen JS (2012) Sustained Hox5 gene activity is required for respiratory motor neuron development. Nat Neurosci 15:1636–1644

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Burgess RW, Jucius TJ, Ackerman SL (2006) Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci. J Neurosci 26:5756–5766

    CAS  PubMed  Google Scholar 

  111. Ja Weiner, Koo SJ, Nicolas S, Fraboulet S, Pfaff SL, Pourquié O, Sanes JR (2004) Axon fasciculation defects and retinal dysplasias in mice lacking the immunoglobulin superfamily adhesion molecule BEN/ALCAM/SC1. Mol Cell Neurosci 27:59–69

    Google Scholar 

  112. McGee AW, Yang Y, Fischer QS, Daw NW, Strittmatter SM (2005) Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science 309:2222–2226

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Dasen JS, Liu J-P, Jessell TM (2003) Motor neuron columnar fate imposed by sequential phases of Hox-c activity. Nature 425:926–933

    CAS  PubMed  Google Scholar 

  114. Dasen JS, Tice BC, Brenner-Morton S, Jessell TM (2005) A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell 123:477–491

    CAS  PubMed  Google Scholar 

  115. Shah V, Drill E, Lance-Jones C (2004) Ectopic expression of Hoxd10 in thoracic spinal segments induces motoneurons with a lumbosacral molecular profile and axon projections to the limb. Dev Dyn 231:43–56

    CAS  PubMed  Google Scholar 

  116. Dasen JS, De Camilli A, Wang B, Tucker PW, Jessell TM (2008) Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1. Cell 134:304–316

    CAS  PubMed  Google Scholar 

  117. Tsuchida T, Ensini M, Morton SB, Baldassare M, Edlund T, Jessell TM (1994) Topographic organization embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79:957–970

    CAS  PubMed  Google Scholar 

  118. Sharma K, Leonard AE, Lettieri K, Pfaff SL (2000) Genetic and epigenetic mechanisms contribute to motor neuron pathfinding. Nature 406:515–519

    CAS  PubMed  Google Scholar 

  119. Tosney KW, Landmesser LT (1985) Growth cone morphology and trajectory in the lumbosacral region of the chick embryo. J Neurosci 5(9):2345–2358

    CAS  PubMed  Google Scholar 

  120. Tosney KW, Landmesser LT (1985) Development of the major pathways for neurite outgrowth in the chick hindlimb. Dev Biol 109:193–214

    CAS  PubMed  Google Scholar 

  121. Landmesser L (1978) The development of motor projection patterns in the chick hind limb. J Physiol 284:391–414

    CAS  PubMed  Google Scholar 

  122. Kania A, Johnson RL, Jessell TM (2000) Coordinate roles for LIM homeobox genes in directing the dorsoventral trajectory of motor axons in the vertebrate limb. Cell 102:161–173

    CAS  PubMed  Google Scholar 

  123. Torre Dalla, di Sanguinetto SA, Dasen JS, Arber S (2008) Transcriptional mechanisms controlling motor neuron diversity and connectivity. Curr Opin Neurobiol 18(1):36–43

    Google Scholar 

  124. Luria V, Krawchuk D, Jessell TM, Laufer E, Kania A (2008) Specification of motor axon trajectory by Ephrin-B:EphB signaling: symmetrical control of axonal patterning in the developing limb. Neuron 60:1039–1053

    CAS  PubMed  Google Scholar 

  125. Kao T-J, Kania A (2011) Ephrin-mediated cis-attenuation of Eph receptor signaling is essential for spinal motor axon guidance. Neuron 71:76–91

    CAS  PubMed  Google Scholar 

  126. Dudanova I, Kao T-J, Herrmann JE, Zheng B, Kania A, Klein R (2012) Genetic evidence for a contribution of EphA:ephrinA reverse signaling to motor axon guidance. J Neurosci 32:5209–5215

    CAS  PubMed  Google Scholar 

  127. Bonanomi D, Chivatakarn O, Bai G, Abdesselem H, Lettieri K, Marquardt T, Pierchala BA, Pfaff SL (2012) Ret is a multifunctional coreceptor that integrates diffusible- and contact-axon guidance signals. Cell 148:568–582

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3:383–394

    CAS  PubMed  Google Scholar 

  129. Kramer ER, Knott L, Su F, Dessaud E, Krull CE, Helmbacher F, Klein R (2006) Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limb. Neuron 50:35–47

    CAS  PubMed  Google Scholar 

  130. Dudanova I, Gatto G, Klein R (2010) GDNF acts as a chemoattractant to support ephrinA-induced repulsion of limb motor axons. Curr Biol 20:2150–2156

    CAS  PubMed  Google Scholar 

  131. Gould TW, Yonemura S, Oppenheim RW, Ohmori S, Enomoto H (2008) The neurotrophic effects of glial cell line-derived neurotrophic factor on spinal motoneurons are restricted to fusimotor subtypes. J Neurosci 28:2131–2146

    CAS  PubMed  Google Scholar 

  132. Huber AB, Kania A, Tran TS, Gu C, De Garcia Marco N, Lieberam I, Johnson D, Jessell TM, Ginty DD, Kolodkin AL (2005) Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Neuron 48:949–964

    CAS  PubMed  Google Scholar 

  133. Moret F, Renaudot C, Bozon M, Castellani V (2007) Semaphorin and neuropilin co-expression in motoneurons sets axon sensitivity to environmental semaphorin sources during motor axon pathfinding. Development 134:4491–4501

    CAS  PubMed  Google Scholar 

  134. Shirasaki R, Lewcock JW, Lettieri K, Pfaff SL (2006) FGF as a target-derived chemoattractant for developing motor axons genetically programmed by the LIM code. Neuron 50:841–853

    CAS  PubMed  Google Scholar 

  135. Gallarda BW, Bonanomi D, Müller D, Brown A, Alaynick WA, Andrews SE, Lemke G, Pfaff SL, Marquardt T (2008) Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science 320:233–236

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Dillon AK, Fujita SC, Matise MP, Jarjour AA, Kennedy TE, Kollmus H, Arnold H-H, Weiner JA, Sanes JR, Kaprielian Z (2005) Molecular control of spinal accessory motor neuron/axon development in the mouse spinal cord. J Neurosci 25(44):10119–10130

    CAS  PubMed  Google Scholar 

  137. Bravo-Ambrosio A, Mastick G, Kaprielian Z (2012) Motor axon exit from the mammalian spinal cord is controlled by the homeodomain protein Nkx2.9 via Robo-Slit signaling. Development 139(8):1435–1446

    CAS  PubMed  Google Scholar 

  138. Wang W, Mullikin-Kilpatrick D, Crandall JE, Gronostajski RM, Litwack ED, Kilpatrick DL (2007) Nuclear factor I coordinates multiple phases of cerebellar granule cell development via regulation of cell adhesion molecules. J Neurosci 27(23):6115–6127

    CAS  PubMed  Google Scholar 

  139. Geisen MJ, Di Meglio T, Pasqualetti M, Ducret S, Brunet J-F, Chedotal A, Rijli FM (2008) Hox paralog group 2 genes control the migration of mouse pontine neurons through slit-robo signaling. PLoS Biol 6(6):e142

    PubMed Central  PubMed  Google Scholar 

  140. Flames N, Hobert O (2009) Gene regulatory logic of dopamine neuron differentiation. Nature 458(7240):885–889

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Kratsios P, Stolfi A, Levine M, Hobert O (2012) Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene. Nat Neurosci 15(2):205–214

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Juan-Pablo Labrador.

Additional information

A. A. Zarin and J. Asadzadeh contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zarin, A.A., Asadzadeh, J. & Labrador, JP. Transcriptional regulation of guidance at the midline and in motor circuits. Cell. Mol. Life Sci. 71, 419–432 (2014). https://doi.org/10.1007/s00018-013-1434-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1434-x

Keywords

Navigation