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Lmx1b is essential for the development of serotonergic neurons

Abstract

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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Figure 1: Expression patterns of Lmx1b, 5-HT and Nkx2-2 in the developing raphe nuclei.
Figure 2: Loss of 5-HT, Pet1 and other 5-HT neuronal markers in Lmx1b−/− mice.
Figure 3: Expression of Shh and transcription factors Nkx2-2 and Phox2b were similar in wild-type (+/+) and Lmx1b−/− mouse embryos (fp, floor plate).
Figure 4: Expression of Lmx1b and Gata3 in Nkx2-2−/− and Pet1−/− mutants.
Figure 5: Comparison of Lmx1b-expressing cells and Lmx1b−/− cells marked by neo staining between wild-type and Lmx1b−/− mice.
Figure 6: A model illustrating genetic pathway controlling 5-HT neuronal development.

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Acknowledgements

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.

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Correspondence to Zhou-Feng Chen.

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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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