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

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During vertebrate development, the specification of distinct cell types is thought to be controlled by inductive signals acting at different concentration thresholds [1].The degree of receptor activation in response to these signals is a known determinant of cell fate [2], 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) [3-5]. These neuronal subtypes derive from distinct progenitor cell populations that express the homeodomain proteins Nkx2.2 or Pax6 in response to graded Shh signalling [6,7]. In mice lacking Pax6, progenitor cells generate neurons characteristic of exposure to greater Shh activity [6,8]. However, Nkx2.2 expression expands dosally in Pax6 mutants [6], 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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