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Volume 16, Number 18, Issue of September 15, 1996 pp. 5727-5740
Copyright ©1996 Society for NeuroscienceA Spatial Gradient of Tau Protein Phosphorylation in Nascent Axons
Received April 10, 1996; revised June 12, 1996; accepted June 27, 1996.
James W. Mandell1, 2 and Gary A. Banker1 Departments of 1 Neuroscience and 2 Pathology, Division of Neuropathology, University of Virginia School of Medicine, Charlottesville, Virginia 22908
Mechanisms underlying axonogenesis remain obscure. Although a large number of proteins eventually become polarized to the axonal domain, in no case does protein compartmentalization occur before or simultaneous with the earliest morphological expression of axonal properties. How then might initially unpolarized proteins, such as the microtubule-associated protein tau, play a role in the microdifferentiation of axons? We hypothesized that tau function could be locally regulated by phosphorylation during the period of axonogenesis. To test this hypothesis, we mapped relative levels of tau phosphorylation within developing cultured hippocampal neurons. This was accomplished using calibrated immunofluorescence ratio measurements employing phosphorylation state-dependent and state-independent antibodies. Tau in the nascent axon is more highly dephosphorylated at the site recognized by the tau-1 antibody than tau in the somatodendritic compartment. The change in phosphorylation state from soma to axon takes the form of a smooth proximo-distal gradient, with tau in the soma, immature dendrites and proximal axon ~80% phosphorylated at the tau-1 site, and that in the axonal growth cone only 20% phosphorylated. The existence of real spatial differences in tau phosphorylation state was confirmed by in situ phosphatase and kinase treatment. Pervanadate, a tyrosine phosphatase inhibitor, induced rapid tau dephosphorylation within live cells, effectively abolishing the phosphorylation gradient. Thus, the gradient is dynamic and potentially regulatable by upstream signals involving tyrosine phosphorylation. Phosphorylation gradients are likely to be present on many neuronal proteins in addition to tau, and their modulation by transmembrane signals could direct the establishment of polarity.
Key words: axonogenesis; polarity; tau; phosphorylation; gradient; microtubule
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