| Coordinated motor behavior has its biological underpinnings in complex neural networks composed of diverse neural subtypes. Essential to how these topographic maps are laid out during development is the generation of neuronal subtype identity, currently believed to be imposed at the post-mitotic level after cells have exited the cell cycle. While there is compelling evidence that motor neuron diversification is regulated by hierarchical transcriptional programs implemented postmitotically, it might not completely be the case.;In this study, we use mice lacking GDE2, a six transmembrane protein, a critical determinant of differentiation, to explore that question. Mice lacking GDE2, a six-transmembrane protein that drives motor neuron generation, exhibit selective deficits of distinct motor neuron subtypes, specifically those that innervate laterally located dorsally derived limb motor pools. These losses correlate with a loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity via a non cell-autonomous feedback loop that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons. |
