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Lmx1b is essential for the development of serotonergic neurons


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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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).

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