Steering Neuronal Growth Cones by Shifting the Imbalance between Exocytosis and Endocytosis

You do expect your doctor to know how to manipulate this axon guidance to redirect neurons around dead areas to connect up sections of your brain again? Don't you?
http://www.jneurosci.org/content/34/21/7165.short

1. Takuro Tojima¹,²,*,
2. Rurika Itofusa¹,*, and
3. Hiroyuki Kamiguchi¹

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1. Author contributions: T.T., R.I., and H.K. designed research; T.T. and R.I. performed research; T.T. and R.I. analyzed data; T.T., R.I., and H.K. wrote the paper.
2. ↵*T.T. and R.I. contributed equally to this work.

1. The Journal of Neuroscience, 21 May 2014, 34(21): 7165-7178; doi: 10.1523/JNEUROSCI.5261-13.2014

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Abstract

Extracellular molecular cues guide migrating growth cones along specific routes during development of axon tracts. Such processes rely on asymmetric elevation of cytosolic Ca²⁺ concentrations across the growth cone that mediates its attractive or repulsive turning toward or away from the side with Ca²⁺ elevation, respectively. Downstream of these Ca²⁺ signals, localized activation of membrane trafficking steers the growth cone bidirectionally, with endocytosis driving repulsion and exocytosis causing attraction. However, it remains unclear how Ca²⁺ can differentially regulate these opposite membrane-trafficking events. Here, we show that growth cone turning depends on localized imbalance between exocytosis and endocytosis and identify Ca²⁺-dependent signaling pathways mediating such imbalance. In embryonic chicken dorsal root ganglion neurons, repulsive Ca²⁺ signals promote clathrin-mediated endocytosis through a 90 kDa splice variant of phosphatidylinositol-4-phosphate 5-kinase type-1γ (PIPKIγ90). In contrast, attractive Ca²⁺ signals facilitate exocytosis but suppress endocytosis via Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (Cdk5) that can inactivate PIPKIγ90. Blocking CaMKII or Cdk5 leads to balanced activation of both exocytosis and endocytosis that causes straight growth cone migration even in the presence of guidance signals, whereas experimentally perturbing the balance restores the growth cone's turning response. Remarkably, the direction of this resumed turning depends on relative activities of exocytosis and endocytosis, but not on the type of guidance signals. Our results suggest that navigating growth cones can be redirected by shifting the imbalance between exocytosis and endocytosis, highlighting the importance of membrane-trafficking imbalance for axon guidance and, possibly, for polarized cell migration in general.