cam-1 (also called
kin-8) is required for cell migration and axon guidance during C. elegans development. In
cam-1 mutants, ALM and CAN neurons fail to migrate posteriorly to their normal destinations. In contrast, the anterior-directed migrations of the HSN and BDU neurons often extend beyond their normal destinations.
cam-1 also is required to properly orient cell polarity.
cam-1 encodes a Ror type receptor tyrosine kinase. Ror kinase family members share three distinct extracellular motifs: immunoglobulin (Ig), cysteine rich domain (CRD), and kringle domain (Kri), as well as intracellular kinase (kin) and Ser/Thr rich regions. To further understand
cam-1 function, we engineered deletions that removed domains individually or in combination and assessed their ability to rescue
cam-1 mutants. Analysis of
cam-1(
gm105) mutants suggested that kinase activity may not be required for its role in cell migration (Forrester et al., Nature 400: 881-5). Consistent with this, we find that a
cam-1 transgene from which the kinase domain is deleted rescues the cell migration defects of animals homozygous for a putative
cam-1 null mutation. Furthermore, we find that the
cam-1 intracellular domain is dispensible for cell migration. These results show that for CAN and HSN cell migration, CAM-1 does not function as a classical receptor tyrosine kinase. Interestingly, a
cam-1 derivative that retains the CRD and membrane spanning region, but that lacks all other domains rescues HSN but not CAN cell migration. The CRD of
cam-1 is similar to that present in members of the frizzled class of Wnt receptors. Wnt binds frizzled via its CRD.
cam-1 interacts genetically with
egl-20, which encodes a Wnt (Maloof et al., Develop. 127: 37-49). Whereas in
cam-1 mutants, the HSNs migrate excessively, in
egl-20 mutants, the HSNs migrate incompletely (Desai et al. Nature 336: 638-46). In animals mutant for both
cam-1 and
egl-20, HSNs migrate to nearly normal positions. These results show that
cam-1 and
egl-20 act in opposition to one another to specify the final positions of migrating HSNs. In animals that overexpress the CRD of
cam-1, HSNs are shifted posteriorly. One intriguing model is that perhaps CAM-1 acts to direct HSNs to their proper position by sequestering EGL-20/Wnt.