Skip to main content

Advertisement

SpringerLink
Log in

Roles of innervation in developing and regenerating orofacial tissues

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

Abstract

The head is innervated by 12 cranial nerves (I–XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kandel ER, Schwartz JH, Jessell TM (2000) Principles of neural science, 4th edn. McGraw-Hill, New York

    Google Scholar 

  2. Rizos M, Negron RJ, Serman N (1998) Möbius syndrome with dental involvement: a case report and literature review. The Cleft Palate Craniofacial J 35(3):262–268. doi:10.1597/1545-1569(1998)035<0262:MBSWDI>2.3.CO;2

    Article  CAS  Google Scholar 

  3. Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisen J (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96(1):25–34

    Article  CAS  PubMed  Google Scholar 

  4. Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433–1438

    Article  CAS  PubMed  Google Scholar 

  5. Mitsiadis TA, Barrandon O, Rochat A, Barrandon Y, De Bari C (2007) Stem cell niches in mammals. Exp Cell Res 313(16):3377–3385. doi:10.1016/j.yexcr.2007.07.027

    Article  CAS  PubMed  Google Scholar 

  6. Jimenez-Rojo L, Granchi Z, Graf D, Mitsiadis TA (2012) Stem cell fate determination during development and regeneration of ectodermal organs. Front Physiol 3:107. doi:10.3389/fphys.2012.00107

    Article  PubMed Central  PubMed  Google Scholar 

  7. Raper J, Mason C (2010) Cellular strategies of axonal pathfinding. Cold Spring Harb Perspect Biol 2(9):a001933. doi:10.1101/cshperspect.a001933

    Article  PubMed Central  PubMed  Google Scholar 

  8. Lai Wing Sun K, Correia JP, Kennedy TE (2011) Netrins: versatile extracellular cues with diverse functions. Development 138(11):2153–2169. doi:10.1242/dev.044529

    Article  PubMed  Google Scholar 

  9. Egea J, Klein R (2007) Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol 17(5):230–238. doi:10.1016/j.tcb.2007.03.004

    Article  CAS  PubMed  Google Scholar 

  10. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361(1473):1545–1564. doi:10.1098/rstb 2006.1894

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7(8):617–627. doi:10.1038/nrn1956

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Schwab ME (2010) Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci 11(12):799–811. doi:10.1038/nrn2936

    Article  CAS  PubMed  Google Scholar 

  13. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659. doi:10.1038/ncb1596

    Article  CAS  PubMed  Google Scholar 

  14. Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Mobius W, Goebbels S, Nave KA, Schneider A, Simons M, Klugmann M, Trotter J, Kramer-Albers EM (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11(7):e1001604. doi:10.1371/journal.pbio.1001604

    Article  PubMed Central  PubMed  Google Scholar 

  15. Thirumangalathu S, Harlow DE, Driskell AL, Krimm RF, Barlow LA (2009) Fate mapping of mammalian embryonic taste bud progenitors. Development 136(9):1519–1528. doi:10.1242/dev.029090

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, Hellekant G, Kinnamon SC (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310(5753):1495–1499. doi:10.1126/science.1118435

    Article  CAS  PubMed  Google Scholar 

  17. Chaudhari N, Roper SD (2010) The cell biology of taste. J Cell Biol 190(3):285–296. doi:10.1083/jcb.201003144

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Okubo T, Pevny LH, Hogan BL (2006) Sox2 is required for development of taste bud sensory cells. Genes Dev 20(19):2654–2659. doi:10.1101/gad.1457106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Lopez GF, Krimm RF (2006) Epithelial overexpression of BDNF and NT4 produces distinct gustatory axon morphologies that disrupt initial targeting. Dev Biol 292(2):457–468. doi:10.1016/j.ydbio.2006.01.021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Oakley B, Witt M (2004) Building sensory receptors on the tongue. J Neurocytol 33(6):631–646. doi:10.1007/s11068-005-3332-0

    Article  PubMed  Google Scholar 

  21. Hosley MA, Hughes SE, Morton LL, Oakley B (1987) A sensitive period for the neural induction of taste buds. J Neurosci 7(7):2075–2080

    CAS  PubMed  Google Scholar 

  22. Yee C, Bartel DL, Finger TE (2005) Effects of glossopharyngeal nerve section on the expression of neurotrophins and their receptors in lingual taste buds of adult mice. J Comp Neurol 490(4):371–390. doi:10.1002/cne.20670

    Article  CAS  PubMed  Google Scholar 

  23. Nosrat CA, Blomlof J, ElShamy WM, Ernfors P, Olson L (1997) Lingual deficits in BDNF and NT3 mutant mice leading to gustatory and somatosensory disturbances, respectively. Development 124(7):1333–1342

    CAS  PubMed  Google Scholar 

  24. Liebl DJ, Mbiene JP, Parada LF (1999) NT4/5 mutant mice have deficiency in gustatory papillae and taste bud formation. Dev Biol 213(2):378–389. doi:10.1006/dbio.1999.9385

    Article  CAS  PubMed  Google Scholar 

  25. Krimm RF, Miller KK, Kitzman PH, Davis BM, Albers KM (2001) Epithelial overexpression of BDNF or NT4 disrupts targeting of taste neurons that innervate the anterior tongue. Dev Biol 232(2):508–521. doi:10.1006/dbio.2001.0190

    Article  CAS  PubMed  Google Scholar 

  26. Patel AV, Huang T, Krimm RF (2010) Lingual and palatal gustatory afferents each depend on both BDNF and NT-4, but the dependence is greater for lingual than palatal afferents. J Comp Neurol 518(16):3290–3301. doi:10.1002/cne.22400

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Nosrat IV, Agerman K, Marinescu A, Ernfors P, Nosrat CA (2004) Lingual deficits in neurotrophin double knockout mice. J Neurocytol 33(6):607–615. doi:10.1007/s11068-005-3330-2

    Article  CAS  PubMed  Google Scholar 

  28. Mbiene JP, Maccallum DK, Mistretta CM (1997) Organ cultures of embryonic rat tongue support tongue and gustatory papilla morphogenesis in vitro without intact sensory ganglia. J Comp Neurol 377(3):324–340

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki Y (2008) Expression of Sox2 in mouse taste buds and its relation to innervation. Cell Tissue Res 332(3):393–401. doi:10.1007/s00441-008-0600-1

    Article  CAS  PubMed  Google Scholar 

  30. Beites CL, Hollenbeck PL, Kim J, Lovell-Badge R, Lander AD, Calof AL (2009) Follistatin modulates a BMP autoregulatory loop to control the size and patterning of sensory domains in the developing tongue. Development 136(13):2187–2197. doi:10.1242/dev.030544

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Hosley MA, Hughes SE, Oakley B (1987) Neural induction of taste buds. J Comp Neurol 260(2):224–232. doi:10.1002/cne.902600206

    Article  CAS  PubMed  Google Scholar 

  32. Proctor GB, Carpenter GH (2007) Regulation of salivary gland function by autonomic nerves. Auton Neurosci 133(1):3–18. doi:10.1016/j.autneu.2006.10.006

    Article  CAS  PubMed  Google Scholar 

  33. Tucker AS (2007) Salivary gland development. Semin Cell Dev Biol 18(2):237–244. doi:10.1016/j.semcdb.2007.01.006

    Article  CAS  PubMed  Google Scholar 

  34. Henriksson R, Carlsoo B, Danielsson A, Sundstrom S, Jonsson G (1985) Developmental influences of the sympathetic nervous system on rat parotid gland. J Neurol Sci 71(2–3):183–191

    Article  CAS  PubMed  Google Scholar 

  35. Coughlin MD (1975) Early development of parasympathetic nerves in the mouse submandibular gland. Dev Biol 43(1):123–139

    Article  CAS  PubMed  Google Scholar 

  36. Knox SM, Lombaert IM, Reed X, Vitale-Cross L, Gutkind JS, Hoffman MP (2010) Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science 329(5999):1645–1647. doi:10.1126/science.1192046

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Murphy RA, Saide JD, Blanchard MH, Young M (1977) Nerve growth factor in mouse serum and saliva: role of the submandibular gland. Proc Natl Acad Sci USA 74(6):2330–2333

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. De Vicente JC, Garcia-Suarez O, Esteban I, Santamaria J, Vega JA (1998) Immunohistochemical localization of neurotrophins and neurotrophin receptors in human and mouse salivary glands. Ann Anat 180(2):157–163. doi:10.1016/S0940-9602(98)80016-2

    Article  PubMed  Google Scholar 

  39. Naesse EP, Schreurs O, Messelt E, Hayashi K, Schenck K (2013) Distribution of nerve growth factor, pro-nerve growth factor, and their receptors in human salivary glands. Eur J Oral Sci 121(1):13–20. doi:10.1111/eos.12008

    Article  CAS  PubMed  Google Scholar 

  40. Ghasemlou N, Krol KM, Macdonald DR, Kawaja MD (2004) Comparison of target innervation by sympathetic axons in adult wild-type and heterozygous mice for nerve growth factor or its receptor trkA. J Pineal Res 37(4):230–240. doi:10.1111/j.1600-079X.2004.00160.x

    Article  PubMed  Google Scholar 

  41. Glebova NO, Ginty DD (2004) Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J Neurosci 24(3):743–751. doi:10.1523/JNEUROSCI.4523-03.2004

    Article  CAS  PubMed  Google Scholar 

  42. Fagan AM, Zhang H, Landis S, Smeyne RJ, Silos-Santiago I, Barbacid M (1996) TrkA, but not TrkC, receptors are essential for survival of sympathetic neurons in vivo. J Neurosci 16(19):6208–6218

    CAS  PubMed  Google Scholar 

  43. Cvekl A, Tamm ER (2004) Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases. BioEssays 26(4):374–386. doi:10.1002/bies.20009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Whitcher JP, Srinivasan M, Upadhyay MP (2001) Corneal blindness: a global perspective. Bull World Health Organ 79(3):214–221

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Vauclair S, Majo F, Durham AD, Ghyselinck NB, Barrandon Y, Radtke F (2007) Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism. Dev Cell 13(2):242–253. doi:10.1016/j.devcel.2007.06.012

    Article  CAS  PubMed  Google Scholar 

  46. Nishida T, Yanai R (2009) Advances in treatment for neurotrophic keratopathy. Curr Opin Ophthalmol 20(4):276–281

    Article  PubMed  Google Scholar 

  47. Muller LJ, Marfurt CF, Kruse F, Tervo TM (2003) Corneal nerves: structure, contents and function. Exp Eye Res 76(5):521–542

    Article  CAS  PubMed  Google Scholar 

  48. McKenna CC, Lwigale PY (2011) Innervation of the mouse cornea during development. Invest Ophthalmol Vis Sci 52(1):30–35. doi:10.1167/iovs.10-5902

    Article  PubMed Central  PubMed  Google Scholar 

  49. Lambiase A, Aloe L, Mantelli F, Sacchetti M, Perrella E, Bianchi P, Rocco ML, Bonini S (2012) Capsaicin-induced corneal sensory denervation and healing impairment are reversed by NGF treatment. Invest Ophthalmol Vis Sci 53(13):8280–8287. doi:10.1167/iovs.12-10593

    Article  CAS  PubMed  Google Scholar 

  50. Ueno H, Ferrari G, Hattori T, Saban DR, Katikireddy KR, Chauhan SK, Dana R (2012) Dependence of corneal stem/progenitor cells on ocular surface innervation. Invest Ophthalmol Vis Sci 53(2):867–872. doi:10.1167/iovs.11-8438

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. de Castro F, Silos-Santiago I, Lopez de Armentia M, Barbacid M, Belmonte C (1998) Corneal innervation and sensitivity to noxious stimuli in trkA knockout mice. Eur J Neurosci 10(1):146–152

    Article  PubMed  Google Scholar 

  52. Mitsiadis TA, Graf D (2009) Cell fate determination during tooth development and regeneration. Birth Defects Res Part C Embryo today 87(3):199–211. doi:10.1002/bdrc.20160

    Article  CAS  Google Scholar 

  53. Luukko K (1997) Immunohistochemical localization of nerve fibres during development of embryonic rat molar using peripherin and protein gene product 9.5 antibodies. Arch Oral Biol 42(3):189–195. doi:10.1016/S0003-9969(97)00004-6

    Article  CAS  PubMed  Google Scholar 

  54. Johnsen DC (1985) Innervation of teeth: qualitative, quantitative, and developmental assessment. J Dental Res 64:555–563

    Google Scholar 

  55. Mohamed SS, Atkinson ME (1983) A histological study of the innervation of developing mouse teeth. J Anat 136(Pt 4):735–749

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Mitsiadis TA, Luukko K (1995) Neurotrophins in odontogenesis. Int J Dev Biol 39(1):195–202

    CAS  PubMed  Google Scholar 

  57. Luukko K, Arumae U, Karavanov A, Moshnyakov M, Sainio K, Sariola H, Saarma M, Thesleff I (1997) Neurotrophin mRNA expression in the developing tooth suggests multiple roles in innervation and organogenesis. Dev Dyn 210(2):117–129. doi:10.1002/(SICI)1097-0177(199710)210:2<117:AID-AJA5>3.0.CO;2-J

    Article  CAS  PubMed  Google Scholar 

  58. Kettunen P, Loes S, Furmanek T, Fjeld K, Kvinnsland IH, Behar O, Yagi T, Fujisawa H, Vainio S, Taniguchi M, Luukko K (2005) Coordination of trigeminal axon navigation and patterning with tooth organ formation: epithelial-mesenchymal interactions, and epithelial Wnt4 and Tgfbeta1 regulate semaphorin 3a expression in the dental mesenchyme. Development 132(2):323–334. doi:10.1242/dev.01541

    Article  CAS  PubMed  Google Scholar 

  59. Pearson AA (1977) The early innervation of the developing deciduous teeth. J Anat 123(Pt 3):563–577

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Loes S, Kettunen P, Kvinnsland H, Luukko K (2002) Mouse rudimentary diastema tooth primordia are devoid of peripheral nerve fibers. Anat Embryol 205(3):187–191. doi:10.1007/s00429-002-0247-8

    Article  PubMed  Google Scholar 

  61. Kollar EJ, Lumsden AG (1979) Tooth morphogenesis: the role of the innervation during induction and pattern formation. Journal de biologie buccale 7(1):49–60

    CAS  PubMed  Google Scholar 

  62. Stainier DY, Gilbert W (1990) Pioneer neurons in the mouse trigeminal sensory system. Proc Natl Acad Sci USA 87(3):923–927

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Lumsden AG, Buchanan JA (1986) An experimental study of timing and topography of early tooth development in the mouse embryo with an analysis of the role of innervation. Arch Oral Biol 31(5):301–311

    Article  CAS  PubMed  Google Scholar 

  64. Tuisku F, Hildebrand C (1994) Evidence for a neural influence on tooth germ generation in a polyphyodont species. Dev Biol 165(1):1–9. doi:10.1006/dbio.1994.1228

    Article  CAS  PubMed  Google Scholar 

  65. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, Frenette PS (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124(2):407–421. doi:10.1016/j.cell.2005.10.041

    Article  CAS  PubMed  Google Scholar 

  66. Brownell I, Guevara E, Bai CB, Loomis CA, Joyner AL (2011) Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell 8(5):552–565. doi:10.1016/j.stem.2011.02.021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Knox SM, Lombaert IM, Haddox CL, Abrams SR, Cotrim A, Wilson AJ, Hoffman MP (2013) Parasympathetic stimulation improves epithelial organ regeneration. Nat Commun 4:1494. doi:10.1038/ncomms2493

    Article  PubMed Central  PubMed  Google Scholar 

  68. Ogawa M, Oshima M, Imamura A, Sekine Y, Ishida K, Yamashita K, Nakajima K, Hirayama M, Tachikawa T, Tsuji T (2013) Functional salivary gland regeneration by transplantation of a bioengineered organ germ. Nat Commun 4:2498. doi:10.1038/ncomms3498

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank the European Science Foundation (ESF) COST Action 1005 NAMABIO for the financial support of the short-term mission No. 020913-033584 (P.P.). This work was supported by the Swiss National Foundation (SNSF) grant 31003A-135633 (T.A.M.), and funds from the University of Zurich (L.J.-R., P.P., T.M.).

Author information

Authors and Affiliations

  1. Faculty of Medicine, Institute of Oral Biology, ZZM, University of Zurich, Plattenstrasse 11, 8032, Zurich, Switzerland

    Pierfrancesco Pagella, Lucia Jiménez-Rojo & Thimios A. Mitsiadis

Authors
  1. Pierfrancesco Pagella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucia Jiménez-Rojo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thimios A. Mitsiadis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thimios A. Mitsiadis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pagella, P., Jiménez-Rojo, L. & Mitsiadis, T.A. Roles of innervation in developing and regenerating orofacial tissues. Cell. Mol. Life Sci. 71, 2241–2251 (2014). https://doi.org/10.1007/s00018-013-1549-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1549-0

Keywords

Search

Navigation