Axonal growth cones contain an unusual IGF-1 receptor with an immunochemically distinct B subunit, Bgc. We have demonstrated that BDNF regulates the distal insertion (at the axonal growth cone) of Bgc in hippocampal neurons. We propose that, in turn, IGF-1 regulates plasmalemmal expansion and, thus, neurite growth by controlling the exocytotic insertion of plasmalemmal precursor vesicles (PPVs). We hypothesize further that there are at least three types of PPVs that may be inserted differentially, and that phosphatidylinositol 3-kinase (PI3k) is involved in the regulation of PPV insertion. We propose to: (i) study membrane expansion at the growth cone in our test tube assay, as well as in intact growth cones in culture using a light microscopic strategy; (ii) characterize the properties of different PPV classes separated by immunoisolation; and (iii) analyze the effects of inhibition of P13k on IGF-1-induced plasmalemmal expansion and potential other growth cone responses. These studies will provide important new information on growth-regulatory events at the growth cone. The new knowledge is expected to enhance our understanding of neuronal network formation in the developing brain and may be applicable to the design of new strategies to enhance nerve regeneration after injury.
| Sosa, Lucas; Dupraz, Sebastian; Laurino, Lisandro et al. (2006) IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nat Neurosci 9:993-5 |
| Laurino, Lisandro; Wang, Xiaoxin X; de la Houssaye, Becky A et al. (2005) PI3K activation by IGF-1 is essential for the regulation of membrane expansion at the nerve growth cone. J Cell Sci 118:3653-62 |
| Pfenninger, Karl H; Laurino, Lisandro; Peretti, Diego et al. (2003) Regulation of membrane expansion at the nerve growth cone. J Cell Sci 116:1209-17 |
