The specification and differentiation of serotonergic (5-HT) neurons require both extrinsic signaling molecules and intrinsic transcription factors to work in concert or in cascade. Here we identify the genetic cascades that control the specification and differentiation of 5-HT neurons in mice. A major determinant in the cascades is an LIM homeodomain-containing gene, Lmx1b, which is required for the development of all 5-HT neurons in the central nervous system. Our results suggest that, during development of 5-HT neurons, Lmx1b is a critical intermediate factor that couples Nkx2-2–mediated early specification with Pet1-mediated terminal differentiation. Moreover, our data indicate that genetic cascades controlling the caudal and rostral 5-HT neurons are distinct, despite their shared components.
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Lauder, J.M., Wallace, J.A., Krebs, H., Petrusz, P. & McCarthy, K. In vivo and in vitro development of serotonergic neurons. Brain Res. Bull. 9, 605–625 (1982).
Jacobs, B.L. & Azmitia, E.C. Structure and function of the brain serotonin system. Physiol. Rev. 72, 165–229 (1992).
Halliday, G., Harding, A. & Paxinos, G. Serotonin and tachykinin systems. In The Rat Nervous System (ed. Paxinos, G.) 929–974 (Academic, Sydney, 1995).
Whitaker-Azmitia, P.M., Druse, M., Walker, P. & Lauder, J.M. Serotonin as a developmental signal. Behav. Brain Res. 73, 19–29 (1996).
Lauder, J.M. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends. Neurosci. 16, 233–240 (1993).
Basbaum, A.I. & Fields, H.L. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu. Rev. Neurosci. 7, 309–338 (1984).
Stockmeier, C.A. Neurobiology of serotonin in depression and suicide. Ann. NY Acad. Sci. 836, 220–232 (1997).
Millan, M.J. Descending control of pain. Prog. Neurobiol. 66, 355–474 (2002).
Hendricks, T.J. et al. Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron 37, 233–247 (2003).
Goridis, C. & Rohrer, H. Specification of catecholaminergic and serotonergic neurons. Nat. Rev. Neurosci. 3, 531–541 (2002).
Ye, W., Shimamura, K., Rubenstein, J.L., Hynes, M.A. & Rosenthal, A. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93, 755–766 (1998).
Hynes, M. & Rosenthal, A. Specification of dopaminergic and serotonergic neurons in the vertebrate CNS. Curr. Opin. Neurobiol. 9, 26–36 (1999).
Chen, H. et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat. Genet. 19, 51–55 (1998).
Smidt, M.P. et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat. Neurosci. 3, 337–341 (2000).
Kania, A., Johnson, R.L. & Jessell, T.M. Coordinate roles for LIM homeobox genes in directing the dorsoventral trajectory of motor axons in the vertebrate limb. Cell 102, 161–173 (2000).
Briscoe, J. et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398, 622–627 (1999).
Blakely, R.D. et al. Cloning and expression of a functional serotonin transporter from rat brain. Nature 354, 66–70 (1991).
Bruning, G., Liangos, O. & Baumgarten, H.G. Prenatal development of the serotonin transporter in mouse brain. Cell Tissue Res. 289, 211–221 (1997).
Nakamoto, H., Soeda, Y., Takami, S., Minami, M. & Satoh, M. Localization of calcitonin receptor mRNA in the mouse brain: coexistence with serotonin transporter mRNA. Brain Res. Mol. Brain Res. 76, 93–102 (2000).
Pfaar, H. et al. mPet-1, a mouse ETS-domain transcription factor, is expressed in central serotonergic neurons. Dev. Genes. Evol. 212, 43–46 (2002).
Hendricks, T., Francis, N., Fyodorov, D. & Deneris, E.S. The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. J. Neurosci. 19, 10348–10356 (1999).
Fyodorov, D., Nelson, T. & Deneris, E. Pet-1, a novel ETS domain factor that can activate neuronal nAchR gene transcription. J. Neurobiol. 34, 151–163 (1998).
van Doorninck, J.H. et al. GATA-3 is involved in the development of serotonergic neurons in the caudal raphe nuclei. J. Neurosci. 19, RC12 (1999).
Yamada, T., Placzek, M., Tanaka, H., Dodd, J. & Jessell, T.M. Control of cell pattern in the developing nervous system: polarizing activity of the floor plate and notochord. Cell 64, 635–647 (1991).
Pattyn, A. et al. Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. Genes Dev. 17, 729–737 (2003).
Briscoe, J., Pierani, A., Jessell, T.M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435–445 (2000).
Chen, Z.F. et al. The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord. Neuron 31, 59–73 (2001).
We thank T. Jessell, J. Brunet, W. Wurst and M. Minami for reagents. We thank E.M. Johnson Jr. and M.F. Jacquin for comments on the manuscript. The project was supported by a NIH grant to Z-F.C. J.E. was supported by the Royal Swedish Academy of Sciences by a donation from the Wallenberg Foundation, The Swedish Foundation for Strategic Research, The Swedish National Research council, Brainstem Genetics: QLRT-2000-01467 and Stembridge: OLG3-CT-2002-01141. E.D. was supported by a NIH grant.
The authors declare no competing financial interests.
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Ding, YQ., Marklund, U., Yuan, W. et al. Lmx1b is essential for the development of serotonergic neurons. Nat Neurosci 6, 933–938 (2003). https://doi.org/10.1038/nn1104
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