TY - JOUR
T1 - GDE2 Regulates Subtype-Specific Motor Neuron Generation through Inhibition of Notch Signaling
AU - Sabharwal, Priyanka
AU - Lee, Changhee
AU - Park, Sungjin
AU - Rao, Meenakshi
AU - Sockanathan, Shanthini
N1 - Funding Information:
We thank Jeremy Dasen, Thomas Jessell, and Ben Novitch for antibodies, Zachary T. Bitzer for technical assistance, Goran Periz for antibody manufacture, members of the Sockanathan laboratory for discussions, and Alex Kolodkin and Ye Yan for comments on the manuscript. This work was funded by grants from the Muscular Dystrophy Association and from the NIH (NINDS RO1NS046336). All experiments involving animals were performed according to procedures approved by the Johns Hopkins IACUC review board.
PY - 2011/9/22
Y1 - 2011/9/22
N2 - The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the 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 through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons.
AB - The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the 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 through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons.
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U2 - 10.1016/j.neuron.2011.07.028
DO - 10.1016/j.neuron.2011.07.028
M3 - Article
C2 - 21943603
AN - SCOPUS:80053113950
SN - 0896-6273
VL - 71
SP - 1058
EP - 1070
JO - Neuron
JF - Neuron
IS - 6
ER -