Nolz1 is induced by retinoid signals and controls motoneuron subtype identity through distinct repressor activities

The acquisition and maintenance of final neuronal identity depends in part upon the implementation of fate-specification programs in postmitotic neurons; however, the mechanisms involved remain unclear. In the developing spinal cord, retinoic acid (RA) signaling pathways specify the columnar and divisional identities of postmitotic motoneurons (MNs). Here we show that RA signals induce expression of the NET transcriptional regulator Nolz1 in differentiated chick MNs, where it regulates the progressive specification of prospective Lim3-negative motor columns. Nolz1 controls the initial formation of forelimb and thoracic Lim3-negative motor columns by downregulating Lim3 expression and maintaining the expression of key homeodomain proteins necessary for MN identity and survival. At forelimb levels, Nolz1 specifies lateral motor column (LMC) identity by inducing the expression of the postmitotic LMC determinant Hoxc6, and implements the partial specification of lateral LMC identity through Lim1 induction. The specificity of Nolz1 function depends upon distinct repressor activities that require, in part, the modulatory activity of Grg5, an atypical member of the Gro-TLE family of co-repressors. Thus, RA signals regulate diverse events in MN subtype specification by inducing the expression of a key transcriptional regulator that controls multiple developmental pathways via functionally distinct repressor complexes.