Independent control of neurogenesis and dorsoventral patterning by NKX2-2.

Human neurogenesis is disproportionately protracted, lasting >10 times longer than in mice, allowing neural progenitors to undergo more rounds of self-renewing cell divisions and generate larger neuronal populations. In the human spinal cord, expansion of the motor neuron lineage is achieved through a newly evolved progenitor domain called the ventral motor neuron progenitor (vpMN) that delays and expands motor neurogenesis. This behavior of vpMNs is controlled by transcription factor NKX2-2, which in vpMNs is coexpressed with classical motor neuron progenitor (pMN) marker OLIG2. In this study, we sought to determine the molecular basis of NKX2-2-mediated extension and expansion of motor neurogenesis. We found that, unlike in mice or chicks, NKX2-2 in the human spinal cord does not repress dorsoventral patterning genes like OLIG2 However, it retains its ability to repress NEUROG2, a proneural gene that promotes exit from the cell cycle and motor neurogenesis. Interestingly, we found that ectopic expression of Tinman mutant Nkx2-2 in mouse pMNs phenocopies human vpMNs, repressing Neurog2 but not Olig2, resulting in delayed motor neurogenesis. Thus, our studies reveal that the classical patterning function of NKX2-2 that depends on its Tinman repressive domain is dissociated from NKX2-2's ability to repress NEUROG2 to control the onset and duration of motor neurogenesis in human ventral motor neuron progenitors.