Genes and Nerves

ABSTRACT

The unpredictability of a brachial plexus graft, a median nerve repair, or a facial-nerve reconstruction is well known. No matter how precise the technical skills, a perfect recovery from a peripheral-nerve lesion is elusive. To resolve this problem, understanding of the normal development of the peripheral nervous system is needed. Presently, the development of the innervation in the upper limb is complex and not fully understood. However, many of the genes involved in this process are now known, and the link between anatomy and genetics is becoming clearer. This short review aims to acquaint the clinical surgeon with some of the main genes. The principal steps in the establishment of neural circuits will be summarized, in particular, the specification and development of neurons and glia, the pathfinding of cells and axons towards their target, and the downstream molecules that control the circuitry of these neurons.

KEYWORDS

Peripheral nervous system - developmental biology - genes

REFERENCES

1 Gene-the entire DNA sequence, including exons, introns, and noncoding transcription-control regions, necessary for production of a functional protein or RNA.

2 Mutation-a permanent heritable change in the nucleotide sequence of a nucleic acid, usually in a single gene, which may lead to a change in or loss of the normal function of the gene product.

3 Commitment-a tissue/cell is inferred to be committed to a specific developmental fate, if it can realize that fate when placed in an environment that is likely to be contradictory.

4 Transgene-a cloned gene that is transferred into and stably incorporated into the animal and is passed on to successive generations.

5 Antisense RNA-an RNA, with sequence complimentary to a specific RNA transcript or mRNA, whose binding prevents processing of the transcript or translation of the mRNA.

6 Morphogen-a type of signaling molecule that acts on cells directly to induce distinct cellular responses in a concentration-dependent manner.

7 Transcription factor-general factors required for transcription of all genes participate in formation of the transcription-initiation complex near the start site; specific factors stimulate (or repress) transcription of particular genes by binding to their regulatory sequences.

8 Growth factor-a molecule that binds to a cell-surface receptor triggering an intracellular signaling pathway leading to proliferation, differentiation, or other cellular response.

9 Gene family-genes which are members of the same family may have fully or partially redundant functions, and their expressions may overlap, temporally and/or spatially. This makes functional analysis difficult.

10 Ligand-any molecule, other than an enzyme substrate, that binds tightly and specifically to a macromolecule, usually a protein, forming a macromolecule-ligand complex.

• 1 Pennacchio L A. Insights from human/mouse genome comparisons.  Mamm Genome. 2003;  14 429-436
• 2 Schoenwolf G C. Cutting, pasting and painting: experimental embryology and neural development.  Nature Rev Neurosci. 2001;  2 763-774
• 3 Roelink H, Tanabe Y, Jessell T M. Sonic hedgehog: a mediator of inductive signaling in the ventral neural tube.  Cell Dev Biol. 1996;  7 121-127
• 4 LeDouarin N M, Kalcheim C. The Neural Crest. Cambridge; Cambridge University Press 1999
• 5 LaBonne C, Bronner-Fraser M. Molecular mechanisms of neural crest formation.  Ann Rev Cell Dev Biol. 1999;  15 81-112
• 6 Thiery J P. Epithelial-mesenchymal transitions in tumour progression.  Nat Rev Cancer. 2002;  2 442-454
• 7 Aybar M J, Nieto M A, Mayor R. Snail precedes Slug in the genetic cascade required for the specification and migration of the Xenopus neural crest.  Development. 2003;  130 483-494
• 8 Nieto M A. The Snail superfamily of zinc-finger transcription factors.  Nat Rev Mol Cell Biol. 2002;  3 155-166
• 9 Nakagawa S, Takeichi M. Neural crest cell-cell adhesion controlled by sequential and subpopulation-specific expression of novel cadherins.  Development. 1995;  121 1321-1332
• 10 Nakagawa S, Takeichi M. Neural crest emigration from the neural tube depends on regulated cadherin expression.  Development. 1998;  125 2963-2971
• 11 Liu J, Jessel T M. A role for rhoB in delamination of neural crest cells from the dorsal neural tube.  Development. 1998;  125 5055-5067
• 12 Hunt P, Guilisano M, Cooke M et al.. A distinct Hox code for the branchial region of the vertebrate head.  Nature. 1991;  353 861-864
• 13 Holland L Z, Holland N D. Expression of AmphiHox1 and AmphiPax1 in amphioxus embryo treated with retinoic acid: insights into evolution and patterning of the chordate nerve cord and pharynx.  Development. 1996;  122 1829-1838
• 14 Liem K F, Tremml G, Jessell T M. A role for the roof plate and its resident TGFbeta-related proteins in neuronal patterning in the dorsal spinal cord.  Cell. 1997;  91 127-138
• 15 Ma Q, Chen Z, del Barco Barrantes I, de al Pompa J L, Anderson D I. Neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia.  Neuron. 1998;  20 469-482
• 16 Fode C, Gradwohl G, Morin X et al.. The bHLH protein Neurogenin 2 is a determination factor for epibranchial placode-derived sensory neurons.  Neuron. 1998;  20 483-494
• 17 Arber S, Ladle D R, Lin J H, Frank E, Jessell T M. ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons.  Cell. 2000;  101 485-498
• 18 Eng S R, Gratwick K, Rhee J M, Fedtsova N, Gan L, Turner E E. Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice.  J Neurosci. 2001;  21 541-549
• 19 Wang H U, Anderson D J. Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth.  Neuron. 1997;  18 383-396
• 20 Krull C E, Lansford R, Gale N W et al.. Interactions of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration.  Curr Biol. 1997;  7 571-580
• 21 Newgreen D F, Powell M E, Moser B. Spatiotemporal changes in HNK-1/L2 glycoconjugates on avian embryo somite and neural crest cells.  Dev Biol. 1990;  139 100-120
• 22 Ranscht B, Bronner-Fraser M. T-Cadherin expression alternates with migrating neural crest cells in the trunk of the avian embryo.  Development. 1991;  111 15-22
• 23 Eickholt B J, Mackenzie S L, Graham A, Walsh F S, Doherty P. Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions.  Development. 1999;  126 2181-2189
• 24 Gross M K, Dottori M, Goulding M. Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord.  Neuron. 2002;  34 535-549
• 25 Muller T, Brohmann H, Pierani A et al.. The homeodomain factor Lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord.  Neuron. 2002;  34 551-562
• 26 Qian Y, Shirasawa S, Chen C L, Cheng L, Ma Q. Proper development of relay somatic sensory neurons and D2/D4 interneurons requires homeobox genes Rnx/Tlx-3 and Tlx-1.  Genes Dev. 2002;  16 1220-1233
• 27 Lin J H, Saito T, Anderson D J, Lance-Jones C, Jessell T M. Functionally related motor neuron pool and muscle afferent subtypes defined by coordinate ETS gene expression.  Cell. 1998;  95 383-407
• 28 Price S R, De Marco Garcia N V, Ranscht B, Jessell T M. Regulation of motor neuron pool sorting by differential expression of type II cadherins.  Cell. 2002;  109 205-216
• 29 Sherrington C S. The Integrative Action of the Nervous System. Cambridge; Cambridge University Press 1906
• 30 Lentz S I, Knudson C M, Korsmeyer S J, Snider W D. Neurotrophins support the development of diverse sensory axon morphologies.  J Neurosci. 1999;  19 1038-1048
• 31 McAllister A K, Katz L C, Lo D C. Neurotrophins and synaptic plasticity.  Ann Rev Neurosci. 1999;  22 295-318
• 32 Goldberg J L, Espinosa J S, Xu Y, Davidson N, Kovacs G T, Barres B A. Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity.  Neuron. 2002;  33 689-702
• 33 Tucker K L, Meyer M, Barde Y A. Neurotrophins are required for nerve growth during development.  Nat Neurosci. 2001;  4 29-37
• 34 Patel T D, Jackman A, Rice F L, Kucera J, Snider W D. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo.  Neuron. 2000;  25 345-357
• 35 Jaaro H, Beck G, Conticello S G, Fainzilber M. Evolving better brains: a need for neurotrophins?.  Trends Neurosci. 2001;  24 79-85
• 36 Davies A M, Bandtlow C, Heumann R, Korsching S, Rohrer H, Thoenen H. Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor.  Nature. 1987;  326 353-358
• 37 Davies A M. Intrinsic programmes of growth and survival in developing vertebrate neurons.  Trends Neurosci. 1994;  17 195-199
• 38 O'Connor R, Tessier-Lavigne M. Identification of maxillary factor, a maxillary process-derived chemoattractant for developing trigeminal sensory axons.  Neuron. 1999;  24 165-178
• 39 Baloh R H, Enomoto H, Johnson Jr E M, Milbrandt J. The GDNF family ligands and receptors - implications for neural development.  Curr Opin Neurobiol. 2000;  10 103-110
• 40 Enomoto H, Crawford P A, Gorodinsky A, Heuckeroth R O, Johnson Jr E M, Milbrandt J. RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons.  Development. 2001;  128 3963-3974
• 41 Honma Y, Araki T, Gianino S et al.. Artemin is a vascular-derived neurotrophic factor for developing sympathetic neurons.  Neuron. 2002;  35 267-282
• 42 Wang H, Tessier-Lavigne M. En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS.  Nature. 1999;  401 765-769
• 43 Hashino E, Shero M, Junghans D, Rohrer H, Milbrandt J, Johnson Jr E M. GDNF and neurturin are target-derived factors essential for cranial parasympathetic neuron development.  Development. 2001;  128 3773-3782
• 44 Ho T W, Bristol L A, Coccia C et al.. TGF beta trophic factors differentially modulate motor axon outgrowth and protection from excitotoxicity.  Exp Neurol. 2000;  161 664-675
• 45 Keller-Peck C R, Feng G, Sanes J R, Yan Q, Lichtman J W, Snider W D. Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction.  J Neurosci. 2001;  21 6136-6146
• 46 Haase G, Dessaud E, Garcés A et al.. GDNF acts through PEA3 to regulate cell body positioning and muscle innervation of specific motor neuron pools.  Neuron. 2002;  35 893-905
• 47 Ebens A, Brose K, Leonardo E D et al.. Hepatocyte growth factor/scatter factor is an axonal chemo-attractant and a neurotrophic factor for spinal motor neurons.  Neuron. 1996;  17 1557-1572
• 48 Maina F, Hilton M C, Ponzetto C, Davies A M, Klein R. Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons.  Genes Dev. 1997;  11 3341-3350
• 49 McFarlane S, McNeill L, Holt C E. FGF signaling and target recognition in the developing Xenopus visual system.  Neuron. 1995;  15 1017-1028
• 50 McFarlane S, Cornel E, Amaya E, Holt C E. Inhibition of FGF receptor activity in retinal ganglion cell axons causes errors in target recognition.  Neuron. 1996;  17 245-254
• 51 Kapfhammer J P, Grunewald B E, Raper J A. The selective inhibition of growth cone extension by specific neurites in culture.  J Neurosci. 1986;  6 2527-2534
• 52 Walter J, Kern-Veits B, Huf J, Stolze B, Bonhoeffer F. Recognition of position-specific properties of tectal cell membranes by retinal axons in vitro.  Development. 1987;  101 685-696
• 53 Stahl B, Muller B, von Boxberg Y, Cox E C, Bonhoeffer F. Biochemical characterization of a putative axonal guidance molecule of the chick visual system.  Neuron. 1990;  5 735-743
• 54 Rothberg J M, Jacobs R J, Goodman C S, Artavanis-Tsakonas S. Slit: an extracellular protein necessary for development of midline glia and commissural axon pathways contains both EGF and LRR domains.  Genes Dev. 1990;  4 2169-2187
• 55 Kidd T, Brose K, Mitchell K J, et a l. Roundabout controls axon crossing of the CNS midline and defines a novel family of evolutionary conserved guidance receptors.  Cell. 1998a;  92 205-215
• 56 Kidd T, Russell C, Goodman S, Tear G. Dosage-sensitive and complementary functions of roundabout and commissureless control axon crossing of the CNS midline.  Neuron. 1998b;  20 25-33
• 57 Brose K, Tessier-Lavigne M. Slit proteins: key regulators of axon guidance, axonal branching, and cell migration.  Curr Opin Neurobiol. 2000;  10 95-102
• 58 Wilkinson D G. Multiple roles of Eph receptors and ephrins in neural development.  Nature Rev Neurosci. 2001;  2 155-164
• 59 Raper J A, Kapfhammer J P. The enrichment of neuronal growth cone collapsing activity from embryonic chick brain.  Neuron. 1990;  4 21-29
• 60 Kolodkin A L, Matthes D J, O'Connor T P et al.. Fasciclin IV: sequence, expression, and function during growth cone guidance in the grasshopper embryo.  Neuron. 1992;  9 831-845
• 61 Kolodkin A L, Mathes D J, Goodman C S. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules.  Cell. 1993;  75 1389-1399
• 62 Luo Y, Raible D, Raper J A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones.  Cell. 1993;  75 217-227
• 63 Bagnard D, Vaillant C, Khuth S T et al.. 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor.  J Neurosci. 2001;  15 3332-3341
• 64 Brown C B, Feiner L, Lu M M et al.. PlexinA2 and Semaphorin signaling during cardiac neural crest development.  Development. 2001;  128 3071-3080
• 65 Feiner L, Webber A L, Brown C B et al.. Targeted disruption of Semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption.  Development. 2000;  128 3061-3070
• 66 Watanabe C, Kumanogoh A, Shi W et al.. Enhanced immune responses in transgenic mice expressing a truncated form of the lymphocyte Semaphorin CD100.  J Immunol. 2001;  167 4321-4328
• 67 Takashima S, Kitakaze M, Asakura M et al.. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis.  Proc Natl Acad Sci USA. 2002;  99 3657-3667
• 68 Tordjman R, Lepelletier Y, Lemarchandel V et al.. A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response.  Nat Immunol. 2002;  3 477-482
• 69 Castellani V, Chedotal A, Schachner M, Faivre-Sarrailh C, Rougon G. Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance.  Neuron. 2000;  27 237-249
• 70 Goshima Y, Nakamura F, Strittmatter P, Strittmatter S M. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33.  Nature. 1995;  376 509-514
• 71 Nakamura F, Kalb R G, Strittmatter S M. Molecular basis of semaphorin-mediated axon guidance.  J Neurobiol. 2000;  44 219-229
• 72 Castellani V, Rougon G. Control of semaphorin signaling.  Curr Opin Neurobiol. 2002;  12 532-541
• 73 Takahashi T, Strittmatter S M. Plexin-A1 autoinhibition by the plexin Sema domain.  Neuron. 2001;  29 429-439
• 74 Nobes C D, Hall A. Rho, Rac and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin fibers, lamellipodia and filopodial.  Cell. 1995;  81 53-62
• 75 Latil A, Chene L, Cochant-Priollet B et al.. Quantification of expression of netrins, slits and their receptors in human prostate tumors.  Int J Cancer. 2003;  103 306-315
• 76 Hedgecock E M, Culotti J G, Hall D H. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans.  Neuron. 1990;  2 61-85
• 77 Keino-Masu K, Masu M, Hinck L et al.. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor.  Cell. 1996;  87 175-185
• 78 Madison R D, Zomorodi A, Robinson G A. Netrin-1 and peripheral nerve regeneration in the adult rat.  Exp Neurol. 2000;  161 563-570
• 79 Zigmond R E, Hyatt-Sachs H, Mohney R P et al.. Changes in neuropeptide phenotype after axotomy of adult peripheral neurons and the role of leukemia inhibitory factor.  Perspect Dev Neurobiol. 1996;  4 75-90
• 80 Fu S Y, Gordon T. The cellular and molecular basis of peripheral nerve regeneration.  Mol Neurobiol. 1997;  14 67-116
• 81 Snider W D, Zhou F Q, Zhong J, Markus A. Signaling the pathway to regeneration.  Neuron. 2002;  35 13-16
• 82 Blesch A, Tuszynski M H. GDNF gene delivery to injured adult CNS motor neurons promotes axonal growth, expression of the trophic neuropeptide CGRP, and cellular protection.  J Comp Neurol. 2001;  436 399-410
• 83 Smith D S, Skene J H. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth.  J Neurosci. 1997;  17 646-658
• 84 Liu R Y, Snider W D. Different signaling pathways mediate regenerative versus developmental sensory axon growth.  J Neurosci. 2001;  21 RC164
• 85 Zhong J, Dietzel I D, Wahle P, Kopf M, Heumann R. Sensory impairments and delayed regeneration of sensory axons in interleukin-6-deficient mice.  J Neurosci. 1999;  19 4305-4313
• 86 Cafferty W B, Gardiner N J, Gavazzi I, et a l. Leukemia inhibitory factor determines the growth status of injured adult sensory neurons.  J Neurosci. 2001;  21 7161-7170
• 87 Coumans J V, Lin T T, Dai H N et al.. Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins.  J Neurosci. 2001;  21 9334-9344
• 88 Ramer M S, Priestley J V, McMahon S B. Functional regeneration of sensory axons into the adult spinal cord.  Nature. 2000;  403 312-316
• 89 Ramer M S, Duraisingam I, Priestley J V, McMahon S B. Two-tiered inhibition of axon regeneration at the dorsal root entry zone.  J Neurosci. 2001;  21 2651-2660
• 90 Romero M I, Rangappa N, Garry M G, Smith G M. Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy.  J Neurosci. 2001;  21 8408-8416
• 91 Yamashita T, Tucker K L, Barde Y A. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth.  Neuron. 1999;  24 585-593
• 92 Yamashita T, Higuchi H, Tohyama M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho.  J Cell Biol. 2002;  157 565-570