Overexpression of PPK-1, the C. elegans Type 1 PIP kinase, inhibits growth cone collapse in the developing nervous system and causes axonal degeneration in adults

• Published in: Developmental biology Vol. 313; no. 1; pp. 384 - 397
• Main Authors: Weinkove, David, Bastiani, Michael, Chessa, Tamara A. M., Joshi, Deepa, Hauth, Linda, Cooke, Frank T., Divecha, Nullin, Schuske, Kim
• Format: Journal Article
• Language: English
• Published: 26.11.2007
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2007.10.029

Growth cones are dynamic membrane structures that migrate to target tissue by rearranging their cytoskeleton in response to environmental cues. The lipid phosphatidylinositol (4,5) bisphosphate (PIP 2 ) resides on the plasma membrane of all eukaryotic cells and is thought to be required for actin cytoskeleton rearrangements. Thus PIP 2 is likely to play a role during neuron development, but this has never been tested in-vivo . In this study we have characterized the PIP 2 synthesizing enzyme Type 1 PIP kinase ( ppk-1 ) in Caenorhabditis elegans . PPK-1 is strongly expressed in the nervous system, and can localize to the plasma membrane. We show that PPK-1 purified from C. elegans can generate PIP 2 in-vitro and that overexpression of the kinase causes an increase in PIP 2 levels in-vivo . In developing neurons, PPK-1 overexpression leads to growth cones that become stalled, produce ectopic membrane projections, and branched axons. Once neurons are established, PPK-1 overexpression results in progressive membrane overgrowth and degeneration during adulthood. These data suggest that overexpression of the Type I PIP kinase inhibits growth cone collapse, and that regulation of PIP 2 levels in established neurons may be important to maintain structural integrity and prevent neuronal degeneration.