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

During vertebrate development, the specification of distinct cell types is thought to be controlled by inductive signals acting at different concentra tion 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 whic h graded signals are converted into all-or-none distinctions in cell identi ty remain poorly resolved. In the ventral neural tube, motor neuron and int erneuron generation depends on the graded activity of the signalling protei n Sonic hedgehog (Shh)(3-5). These neuronal subtypes derive from distinct p rogenitor cell populations that express the homeodomain proteins Nkx2.2 or Pax6 in response to graded Shh signalling(6,7). In mice lacking Pax6, proge nitor cells generate neurons characteristic of exposure to greater Shh acti vity(6,8). However, Nkx2.2 expression expands dosally in Pax6 mutants(6), r aising the possibility that Pax6 controls neuronal pattern indirectly. Here we provide evidence that Nkx2.2 has a primary role in ventral neuronal pat terning. In Nkx2.2 mutants, Pax6 expression is unchanged but cells undergo a ventral-to-dorsal transformation in fate and generate motor neurons rathe r than interneurons. Thus, Nkx2.2 has an essential role in interpreting gra ded Shh signals and selecting neuronal identity.