Neurons Finding Their Way with Kinase and Staying There Without

Abstract

During nervous system development, growing axons must find their way to the appropriate regions and, once they have arrived, must remain in the proper place. Bülow et al. used genetic analysis to investigate the role of the Caenorhabditis elegans fibroblast growth factor receptor, EGL-15 (a receptor tyrosine kinase), in axonal pathfinding and maintenance of axonal position. C. elegans larvae that completely lacked EGL-15 activity showed defects in the extension (premature termination) and guidance (midline crossover defects) of ventral midline axons. Reducing EGL-15 activity with a hypomorphic allele or reducing the activity of the downstream guanosine triphosphatase LET-60 (Ras homolog) led to defects in axon guidance, whereas constitutively active let-60 allele rescued defects in axon extension in larvae lacking EGL-15 activity. Experiments with egl-15 gene reporters and with expression of egl-15 or let-60 under the control of tissue-specific promoters indicated that EGL-15 acted in the cells of the hypodermis (over which ventral nerve cord neurons grow) to affect axon outgrowth. Worms expressing a mutant allele that eliminated the activity of only one EGL-15 isoform, EGL-15(5A), showed no defects in embryonic axon extension or guidance but did exhibit position defects in adults, indicating a deficit in maintenance. A catalytically inactive mutant of EGL-15(5A) could not rescue the developmental defects that accompany loss of EGL-15 activity but could rescue the defects in maintenance produced by loss of egl-15(5A) . Further, a construct that encoded a secreted form of the EGL-15(5A) ectodomain rescued these maintenance defects. Thus, EGL-15 appears to affect axon navigation and positional maintenance through distinct mechanisms, one of which is independent of its tyrosine kinase activity. H. Bülow, T. Boulin, O. Hobert, Differential functions of the C. elegans FGF receptor in axon outgrowth and maintenance of axon position. Neuron 42 , 367-374 (2004). [Online Journal]