The paired-like homeobox genes Phox2a and Phox2b are involved in neuronal subtype specification in the mouse (1,2). The Phox2 orthologue in C. elegans, called
ceh-17 , encodes a protein with 88% identity in the homeodomain to murine Phox2a and Phox2b (3). CEH-17 is expressed in five head neurons, ALA and the 4 SIAs, which project axons towards the tail along the lateral and sublateral cords respectively. Expression starts at the late proliferative stage, and is strongest during axonal elongation from the comma to the three-fold stage. The function of these five neurons is still unknown, and their synaptic connectivity incompletely resolved. Abrogation of
ceh-17 function disrupts posterior axonal elongation of both ALA and SIA axons beyond the mid-body region. A fully penetrant stalling phenotype was observed for the ALA axons with more than 80% of them stopping within one body diameter of the gonad primordium. Conversely, ectopic expression of
ceh-17 in the mechanoreceptors, using the
mec-3 promoter, leads to exaggerated longitudinal axonal outgrowth. The PLM axons, instead of stopping at the level of the ALM cell body, reached a position anterior to the AVM cell body, and were occasionally more than twice their normal length, extending as far as the nerve ring. This ectopic outgrowth did not fasciculate with the sublateral ventral or the lateral cords, but pioneered its own extension. As to the AVM axon, most often its exaggerated anteriorward progress was stopped only when it reached the nose, whereupon it frequently turned back and grew posteriorly. Another phenotype was the growth of a posteriorly directed axon from the ALM cell body. We also ectopically expressed
ceh-17 using the
glr-1 promoter, which directs expression in several head and tail neuronal classes. In
pglr-1::
ceh-17 animals, an unidentified
glr-1 + head neuron was seen projecting abnormally beyond the nerve ring towards the head, sometimes as far as the nose. In addition, PVQ acquired a posterior projection never seen in wild type. Altogether these gain-of-function data show that ectopic
ceh-17 is sufficient to induce cell-autonomous excessive longitudinal axonal outgrowth, both anteriorly and posteriorly, in many neurons. A hypothesis, compatible with both gain and loss-of-function phenotypes is a role of
ceh-17 in blinding the growth cone to a stop signal. Thus, in the absence of
ceh-17 , an otherwise cryptic signal from the mid-body region would induce the ALA and SIA growth cones to stop. Conversely, in the presence of
ceh-17 , the mechanoreceptors would ignore the stop signal(s) which normally locate the tip of their axons at precise positions on the antero-posterior axis. It is conceivable that, whatever the signal and its source, there is a generic stalling process at play inside every neuron -possibly related to growth cone collapse- that
ceh-17 impinges on. We are currently screening for suppressors of the
ceh-17 gain-of-function in
glr-1 neurons to identify co-factors and targets of CEH-17. The screen is based on the recovery of wild type movement in
pglr-1::
ceh-17 worms which paradoxically go backward after a tap on the tail. (1) Morin et al. 97, Neuron, 18, 411-423 (2) Pattyn et al. 99, Nature, 399, 366-370 (3) Pujol et al. 00, Development, 127, 3361-3371.