The ability of cells to invade through basement membranes is crucial during development and in the progression of metastatic cancer. The regulatory circuits that control invasive behavior, however, remain poorly understood because of the lack of in vivo models where this process can be both visualized and genetically dissected. Anchor cell (AC) invasion in C. elegans is a new model of cell-invasive behavior where such analysis is now possible. Connection of the uterus and vulva in C. elegans is initiated by the uterine AC, whose basolateral portion crosses the basement membranes separating both tissues, and then invades between the central vulval cells. Anchor cell invasion is regulated by: (1) the precise removal of the basement membranes by the AC during invasion; (2) a diffusible cue generated by the central vulval cells that stimulates and targets invasion; (3) production of mesenchymal-like invasive protrusions in the basolateral region of the AC. I have found that in
fos-1 (formerly
evl-5) mutants, AC invasion is absent or severely delayed. Visualization of the AC behavior revealed that it extends cellular processes toward vulval cells, and thus remains attracted to its target. However, the processes flatten at an intact basement membrane, indicating an inability to breach this barrier.
fos-1 encodes the C. elegans ortholog of the proto-oncogene transcription factor fos.
fos-1 generates two transcripts utilizing distinct start exons,
fos-1a and
fos-1b. The
fos-1(
ar105) allele selectively disrupts
fos-1a. FOS-1A is primarily expressed in somatic gonad cells, and is present at high levels in the AC during invasion. Furthermore, AC-specific expression of FOS-1A, but not FOS-1B, rescues invasion in
fos-1(
ar105) mutants, confirming cell-autonomous function in the AC. I have also identified ZMP-1, a membrane-type matrix metalloproteinase, CDH-3, a Fat-like protocadherin, and hemicentin, a fibulin family extracellular matrix protein, as transcriptional targets of
fos-1a. The localization of these proteins in the AC suggests they might play direct roles in promoting removal of the basement membrane. Animals containing null mutations in
zmp-1,
cdh-3 and
him-4 (hemicentin) show subtle delays in AC invasion, indicating they function redundantly with other targets of
fos-1a not yet identified. These studies reveal an in vivo role for the Fos transcription factor in regulating basement membrane removal during a cell invasion event and begin to identify the downstream targets that mediate breaching of the basement membrane.