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Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling

Abstract

During vertebrate development, the specification of distinct cell types is thought to be controlled by inductive signals acting at different concentration thresholds1. The degree of receptor activation in response to these signals is a known determinant of cell fate2, but the later steps at which graded signals are converted into all-or-none distinctions in cell identity remain poorly resolved. In the ventral neural tube, motor neuron and interneuron generation depends on the graded activity of the signalling protein Sonic hedgehog (Shh)3,4,5. These neuronal subtypes derive from distinct progenitor cell populations that express the homeodomain proteins Nkx2.2 or Pax6 in response to graded Shh signalling6,7. In mice lacking Pax6, progenitor cells generate neurons characteristic of exposure to greater Shh activity6,7. However, Nkx2.2 expression expands dosally in Pax6 mutants6, raising the possibility that Pax6 controls neuronal pattern indirectly. Here we provide evidence that Nkx2.2 has a primary role in ventral neuronal patterning. In Nkx2.2 mutants, Pax6 expression is unchanged but cells undergo a ventral-to-dorsal transformation in fate and generate motor neurons rather than interneurons. Thus, Nkx2.2 has an essential role in interpreting graded Shh signals and selecting neuronal identity.

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Figure 1: Nkx2.2 and Nkx2.9 are expressed in the ‘x’ domain of the neural tube.
Figure 2: Nkx2.2 activity is not required for the establishment of progenitor cell domains in the ventral neural tube.
Figure 4: Nkx2.2 represses somatic motor neuron generation in the ‘x’ domain of the spinal cord.
Figure 3: Nkx2.2 activity is required for the generation of V3 neurons.
Figure 5: Nkx2.2 is required for the generation of hindbrain serotonergic neurons but not visceral motor neurons.
Figure 6: Distinct roles for Nkx2.2 and Pax6 in the control of ventral neuronal identity in response to graded Sonic hedgehog signalling.

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Acknowledgements

We thank P. Rashbass and V. van Heyningen for Sey mice; D. Anderson, J. F. Brunet, H. Edlund, C. Goridis, A. Frankfurter, C. William and S. Wilson for reagents; C. Doe for results on vnd; R.Axel, K. Lee and G. Struhl for comments on the manuscript; and K. MacArthur for help in preparating the manuscript. This work was supported by grants to T.M.J. from the NIH and to J.L.R.R. from Nina Ireland, NARSAD and NIMH; by an HFSP fellowship (J.B.); by the Swedish Institute, the Swedish Foundation for Strategic Research, and the Swedish National Research Council (J.E.); by the Bank of America, Scottish Rite and NIH, NRSA (L.S.); and by the Danish National Research Foundation (P.S.). J.B. and J.E. are associates and T.M.J. is an investigator of the Howard hughes Medical Institute.

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Briscoe, J., Sussel, L., Serup, P. et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398, 622–627 (1999). https://doi.org/10.1038/19315

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