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