Neurons exhibit the most marked size differences and diversity in intrinsic growth rates of any class of cells. How then can a neuron coordinate between biosynthesis rates in the soma and the growth needs of different lengths of axons? The central hypothesis of this proposal is that neurons sense the lengths of the axonal microtubule cytoskeleton on an ongoing basis by bidirectional motor-dependent axon-nucleus communication, and that the oscillating retrograde signal generated by this mechanism provides input for the coordinated regulation of neuronal biosynthesis and axonal growth. We will test this hypothesis in a multidisciplinary work program that will characterize and quantify the link between biosynthesis levels and axon outgrowth rates and identify and validate the roles and functions of key molecules underlying this mechanism. This research program will elucidate how neuronal biosynthesis and axon growth are co-regulated. New mechanistic insights on this fundamental aspect of neuronal cell biology will have far-reaching implications. From the basic science perspective, this work will establish a new modality for encoding spatial information in biological signals, providing a one-dimensional solution to the three-dimensional problem of sensing cell size. Moreover, the proposed mechanism can explain intrinsic limits on regenerative neuronal growth and raises the intriguing possibility of opening new avenues to bypass such limits towards acceleration of axonal growth for effective neural repair.
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