Skip to main content
Log in

Specification and differentiation of serotonergic neurons

  • Original Article
  • Published:
Stem Cell Reviews Aims and scope Submit manuscript

Abstract

Serotonin is an important neurotransmitter with multiple functions in the whole central nervous system. Its synthesis, however, is restricted to a very limited number of cells in the brainstem raphe nuclei with a vast axonal network. These cells express markers of the serotonin lineage such as the rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase 2, the serotonin transporter, and the transcription factor Pet1. Pet1 together with Lmx1b, Nkx2.2, Mash1, Gata2, Gata3, and Phox2b form a transcriptional network, which specifies the differentiation of serotonergic neurons around embryonic day 11 in the mouse. These cells are generated in rhombomeres r1–r3 and r5–r7 caudal to the midbrain-hindbrain organizer under the control of the fibroblast growth factors 4 and 8 and sonichedgehog (SHH) from precursors, which have produced motoneurons before. Because serotonin is a relevant pathophysiological factor in several neurological diseases such as bipolar disorder and depression tools to generate or maintain serotonergic neurons might be of therapeutic value. Such tools can be assessed in embryonic stem cells, which can be differentiated in vitro to produce serotonergic neurons. Culture systems for these cells including embryoid bodies based and monolayer differentiation have been established, which allows the generation of up to 50% serotonergic neurons in all neurons developed.

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.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

5-HT:

Serotonin (5-hydroxytryptamine)

AA:

Ascorbic acid

AAAD:

Aromatic amino acid decarboxylase

AGM:

Aorta-gonad-mesonephros

BDNF:

Brain-derived neurotrophic factor

bHLH:

Basic-helix-loop-helix

E14:

Embryonic day 14

EBs:

Embryoid bodies

ES cells:

Embryonic stem cells

FCS:

Fetal calf serum

FGF:

Fibroblast growth factor

Gata:

GATA-motif binding

ITSFn:

Insulin-transferrin-selenium-fibronectin-medium

KSR:

Knockout serum replacement

LIF:

Leukemia inhibitory factor

Lmx1b:

LIM homeobox transcription factor 1β

Mash1:

Mouse achaete-scute homolog 1

MHO:

Midbrain-hindbrain organizer

Nkx2.2:

NK transcription factor related, locus 2

NSCs:

Neural stem cells

PDL/Lam:

Poly-d-lysine/laminin

Pet1:

Pheochromocytoma 12 ETS

Phox2b:

Paired-like homeodomain protein 2b

PLO/Lam:

Poly-l-ornithine/laminin

SDIA:

Stromal cell-derived inducing activity

RA:

Retinoic acid

SERT:

Serotonin transporter

SHH:

Sonic hedgehog

TGF-β:

Transforming growth factor-β

TPH:

Tryptophan hydroxylase

VMAT2:

Vesicular monoamine transporter 2

References

  1. Matsuda M, Imaoka T, Vomachka AJ, et al. Dev Cell 2004;6: 193–203.

    Article  PubMed  CAS  Google Scholar 

  2. Walther DJ, Peter JU, Bashammakh S, et al. Science 2003;299:76.

    Article  PubMed  CAS  Google Scholar 

  3. Walther DJ, Peter JU, Winter S, et al. Cell 2003;115:851–862.

    Article  PubMed  CAS  Google Scholar 

  4. Richerson GB. Nat Rev Neurosci 2004;5:449–461.

    Article  PubMed  CAS  Google Scholar 

  5. Dahlstrom A, Fuxe K. Experientia 1964;20:398–399.

    Article  PubMed  CAS  Google Scholar 

  6. Brodski C, Weisenhorn DM, Signore M, et al. J Neurosci 2003;23: 4199–4207.

    PubMed  CAS  Google Scholar 

  7. Ye W, Bouchard M, Stone D, et al. Nat Neurosci 2001;4:1175–1181.

    Article  PubMed  CAS  Google Scholar 

  8. Ye W, Shimamura K, Rubenstein JL, Hynes MA, Rosenthal A. Cell 1998;93:755–766.

    Article  PubMed  CAS  Google Scholar 

  9. Pattyn A, Vallstedt A, Dias JM, et al. Genes Dev 2003;17:729–737.

    Article  PubMed  CAS  Google Scholar 

  10. Pattyn A, Simplicio N, van Doorninck JH, Goridis C, Guillemot F, Brunet JF. Nat Neurosci 2004;7:589–595.

    Article  PubMed  CAS  Google Scholar 

  11. Hendricks T, Francis N, Fyodorov D, Deneris ES. J Neurosci 1999;19:10,348–10,356.

    CAS  Google Scholar 

  12. Hendricks TJ, Fyodorov DV, Wegman LJ, et al. Neuron 2003; 37:233–247.

    Article  PubMed  CAS  Google Scholar 

  13. Brunet JF, Pattyn A. Curr Opin Genet Dev 2002;12:435–440.

    Article  PubMed  CAS  Google Scholar 

  14. Samad OA, Geisen MJ, Caronia G, et al. Development 2004;131:4071–4083.

    Article  PubMed  CAS  Google Scholar 

  15. Blaugrund E, Pham TD, Tennyson VM, et al. Development 1996, 122:309–320.

    PubMed  CAS  Google Scholar 

  16. Briscoe J, Sussel L, Serup P, et al. Nature 1999;398:622–627.

    Article  PubMed  CAS  Google Scholar 

  17. Ding YQ, Marklund U, Yuan W, et al. Nat Neurosci 2003;6: 933–938.

    Article  PubMed  CAS  Google Scholar 

  18. Cheng L, Chen CL, Luo P, et al. J Neurosci 2003;23:9961–9967.

    PubMed  CAS  Google Scholar 

  19. Smidt MP, Asbreuk CH, Cox JJ, Chen H, Johnson RL, Burbach JP. Nat Neurosci 2000;3:337–341.

    Article  PubMed  CAS  Google Scholar 

  20. Scott MM, Wylie CJ, Lerch JK, et al. Proc Natl Acad Sci USA 2005;102:16,472–16,477.

    CAS  Google Scholar 

  21. Patient RK, McGhee JD. CurrOpin Genet Dev 2002;12:416–422.

    Article  CAS  Google Scholar 

  22. Craven SE, Lim KC, Ye W, Engel JD, de Sauvage F, Rosenthal A. Development 2004;131:1165–1173.

    Article  PubMed  CAS  Google Scholar 

  23. van Doorninck JH, van Der WJ, Karis A, et al. J Neurosci 1999; 19:RC12.

    Google Scholar 

  24. Evans MJ, Kaufman MH. Nature 1981;292:154–156.

    Article  PubMed  CAS  Google Scholar 

  25. Martin GR. Proc Natl Acad Sci USA 1981;78:7634–7638.

    Article  PubMed  CAS  Google Scholar 

  26. Wobus AM, Holzhausen H, Jakel P, Schoneich. J Exp Cell Res 1984;152:212–219.

    Article  CAS  Google Scholar 

  27. Kawase E, Yamazaki Y, Yagi T, Yanagimachi R, Pedersen RA. Genesis 2000;28:156–163.

    Article  PubMed  CAS  Google Scholar 

  28. Munsie MJ, Michalska AE, O'Brien CM, Trounson AO, Pera MF, Mountford PS. Curr Biol 2000;10:989–992.

    Article  PubMed  CAS  Google Scholar 

  29. Wakayama T, Tabar V, Rodriguez I, Perry AC, Studer L, Mombaerts P. Science 2001;292:740–743.

    Article  PubMed  CAS  Google Scholar 

  30. Tada M, Morizane A, Kimura H, et al. Dev Dyn 2003;227:504–510.

    Article  PubMed  CAS  Google Scholar 

  31. Bain G, Kitchens D, Yao M, Huettner JE, Gottlieb DI. Dev Biol 1995;168:342–357.

    Article  PubMed  CAS  Google Scholar 

  32. Fraichard A, Chassande O, Bilbaut G, Dehay C, Savatier P, Samarut J. J Cell Sci 1995;108(Pt 10):3181–3188.

    PubMed  CAS  Google Scholar 

  33. Strubing C, Ahnert-Hilger G, Shan J, Wiedenmann B, Hescheler J, Wobus AM. Mech Dev 1995;53:275–287.

    Article  PubMed  CAS  Google Scholar 

  34. Bain G, Ray WJ, Yao M, Gottlieb DL. Biochem Biophys Res Commun 1996;223:691–694.

    Article  PubMed  CAS  Google Scholar 

  35. Guan K, Chang H, Rolletschek A, Wobus AM. Cell Tissue Res 2001;305:171–176.

    Article  PubMed  CAS  Google Scholar 

  36. Kawasaki H, Mizuseki K, Nishikawa S, et al. Neuron 2000; 28:31–40.

    Article  PubMed  CAS  Google Scholar 

  37. Cazillis M, Gonzalez BJ, Billardon C, et al. Eur J Neurosci 2004; 19:798–808.

    Article  PubMed  Google Scholar 

  38. Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD. Nat Biotechnol 2000;18:675–679.

    Article  PubMed  CAS  Google Scholar 

  39. Hynes M, Rosenthal A. Neuron 2000;28:11–14.

    Article  PubMed  CAS  Google Scholar 

  40. Sonntag KC, Simantov R, Isacson O. Brain Res Mol Brain Res 2005;134:34–51.

    Article  PubMed  CAS  Google Scholar 

  41. Arenas E. Brain Res Bull 2002;57:795–808.

    Article  PubMed  CAS  Google Scholar 

  42. Hynes M, Rosenthal A. Curr Opin Neurobiol 1999;9:26–36.

    Article  PubMed  CAS  Google Scholar 

  43. Galter D, Bottner M, Unsicker K. J Neurosci Res 1999;56:531–538.

    Article  PubMed  CAS  Google Scholar 

  44. Galter D, Unsicker K. Mol Cell Neurosci 2000;15:446–455.

    Article  PubMed  CAS  Google Scholar 

  45. Rumajogee P, Madeira A, Verge D, Hamon M, Miquel MC. J Neurochem 2002;83:1525–1528.

    Article  PubMed  CAS  Google Scholar 

  46. Rumajogee P, Verge D, Darmon M, Brisorgueil MJ, Hamon M, Miquel MC. J Neurosci Res 2005;81:481–487.

    Article  PubMed  CAS  Google Scholar 

  47. Djalali S, Holtje M, Grosse G, et al. J Neurchem 2005;92:616–627.

    Article  CAS  Google Scholar 

  48. Watanabe K, Kamiya D, Nishiyama A, et al. Nat Neurosci 2005;8:288–296.

    Article  PubMed  CAS  Google Scholar 

  49. Bottenstein JE, Sato GH. Proc. Natl Acad Sci USA 1979;76:514–517.

    Article  PubMed  CAS  Google Scholar 

  50. Ying QL, Stavridis M, Griffiths D, Li M, Smith A. Nat Biotechnol 2003;21:183–186.

    Article  PubMed  CAS  Google Scholar 

  51. Wiles MV, Johansson BM. Exp Cell Res 1999;247:241–248.

    Article  PubMed  CAS  Google Scholar 

  52. Tropepe V, Hitoshi S, Sirard C, Mak TW, Rossant J, van der KD. Neuron 2001;30:65–78.

    Article  PubMed  CAS  Google Scholar 

  53. Okabe S, Forsberg-Nilsson K, Spiro AC, Segal M, McKay RD. Mech Dev 1996;59:89–102.

    Article  PubMed  CAS  Google Scholar 

  54. Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al. Nature 2002;418:50–56.

    Article  PubMed  CAS  Google Scholar 

  55. Salli U, Reddy AP, Salli N, et al. Exp Neurol 2004;188:351–364.

    Article  PubMed  CAS  Google Scholar 

  56. Barberi T, Klivenyi P, Calingasan NY, et al. Nat Biotechnol 2003;21:1200–1207.

    Article  PubMed  CAS  Google Scholar 

  57. Stavridis MP, Smith AG. Biochem Soc. Trans 2003;31:45–49.

    Article  PubMed  CAS  Google Scholar 

  58. Wang W, Bradley SR, Richerson GB. J Physiol 2002;540:951–970.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Bader.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alenina, N., Bashammakh, S. & Bader, M. Specification and differentiation of serotonergic neurons. Stem Cell Rev 2, 5–10 (2006). https://doi.org/10.1007/s12015-006-0002-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-006-0002-2

Index Entries

Navigation