Inductive signaling leads to the coactivation of regulatory pathways for specifying general neuronal traits in parallel with instructions for neuronal subtype specification. Nevertheless, the mechanisms that ensure that these pathways are synchronized have not been defined. To address this, we examined how bHLH proteins Ngn2 and NeuroM controlling neurogenesis functionally converge with LIM-homeodomain (LIM-HD) factors Isl1 and Lhx3 involved in motor neuron subtype specification. We found that Ngn2 and NeuroM transcriptionally synergize with Isl1 and Lhx3 to specify motor neurons in the embryonic spinal cord and in P19 stem cells. The mechanism underlying this cooperativity is based on interactions that directly couple the activity of the bHLH and LIM-HD proteins, mediated by the adaptor protein NLI. This functional link acts to synchronize neuronal subtype specification with neurogenesis.
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