Neurogenin3 is a key regulator in serotoninergic vs. spinal V3 neuronal fate decisions

CARCAGNO, A; DI BELLA, D; LANUZA, G.M.

San Diego

Congreso; Neuroscience 2013 - Meeting of the Society for Neuroscience; 2013

Society for Neuroscience

The mechanisms that control lineage specification in the developing central nervous system are not completely understood. Studies from the last decade have shown that neural progenitor cells integrate extrinsic signals by inducing genetic programs largely controlled by the Combinatorial action of transcription factors in precursors along orthogonal axes. The most ventral domain of neural tube progenitors, termed p3, produces serotonergic and glutamatergic V3 interneurons in the hindbrain and the spinal cord, respectively. We found that these two equivalents progenitor domains are distinct in their expression of the bHLH transcription factors Neurog3 and Ascl1. Neurog3 expression along the rostrocaudal axis correlates with the development of spinal V3 interneurons. On the other hand, Ascl1 controls the specification of serotonergic neurons in the hindbrain. We propose that Neurog3 suppresses serotonergic neuronal cell fate in the spinal cord through the downregulation of Ascl1. In order to test this hypothesis, we performed electroporations in the chick neural tube and found that Neurog3 is able to repress Ascl1 expression and serotonergic differentiation in thehindbrain. In addition, the analysis of mice lacking Neurog3 showed that ventral Nkx2.2+ spinal cord progenitors development into ectopic serotonergic neurons at expenses of V3 interneurons. In Neurog3-/- embryos, differentiating serotonergic cells, marked by Gata2, Lmx1b and Pet1, originate from ventral spinal cord cells that highly express Ascl1, contrary to wild type progenitors. In summary, our results show that Neurogenin3 is a key regulator in the restricting serotonergic neuron development to the hindbrain and allows differentiation of spinal motorrelated V3 interneurons.