Hajnal A, Whitfield C W, Kim S K
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305 USA.
Genes Dev. 1997 Oct 15;11(20):2715-28. doi: 10.1101/gad.11.20.2715.
During induction of the Caenorhabditis elegans hermaphrodite vulva, a signal from the anchor cell activates the LET-23 epidermal growth factor receptor (EGFR)/LET-60 Ras/MPK-1 MAP kinase signaling pathway in the vulval precursor cells. We have characterized two mechanisms that limit the extent of vulval induction. First, we found that gap-1 may directly inhibit the LET-60 Ras signaling pathway. We identified the gap-1 gene in a genetic screen for inhibitors of vulval induction. gap-1 is predicted to encode a protein similar to GTPase-activating proteins that likely functions to inhibit the signaling activity of LET-60 Ras. A loss-of-function mutation in gap-1 suppresses the vulvaless phenotype of mutations in the let-60 ras signaling pathway, but a gap-1 single mutant does not exhibit excess vulval induction. Second, we found that let-23 EGFR prevents vulval induction in a cell-nonautonomous manner, in addition to its cell-autonomous role in activating the let-60 ras/mpk-1 signaling pathway. Using genetic mosaic analysis, we show that let-23 activity in the vulval precursor cell closest to the anchor cell (P6.p) prevents induction of vulval precursor cells further away from the anchor cell (P3.p, P4.p, and P8.p). This result suggests that LET-23 in proximal vulval precursor cells might bind and sequester the inductive signal LIN-3 EGF, thereby preventing diffusion of the inductive signal to distal vulval precursor cells.
在秀丽隐杆线虫雌雄同体外阴诱导过程中,来自锚定细胞的信号激活外阴前体细胞中的LET-23表皮生长因子受体(EGFR)/LET-60 Ras/MPK-1丝裂原活化蛋白激酶信号通路。我们已经鉴定出两种限制外阴诱导程度的机制。首先,我们发现gap-1可能直接抑制LET-60 Ras信号通路。我们在一项针对外阴诱导抑制剂的遗传筛选中鉴定出了gap-1基因。gap-1预计编码一种类似于GTP酶激活蛋白的蛋白质,其可能发挥抑制LET-60 Ras信号活性的作用。gap-1的功能丧失突变抑制了let-60 ras信号通路中突变的无外阴表型,但gap-1单突变体并未表现出过度的外阴诱导。其次,我们发现let-23 EGFR除了在激活let-60 ras/mpk-1信号通路中发挥细胞自主作用外,还以细胞非自主方式阻止外阴诱导。通过遗传镶嵌分析,我们表明最靠近锚定细胞的外阴前体细胞(P6.p)中的let-23活性可阻止远离锚定细胞的外阴前体细胞(P3.p、P4.p和P8.p)的诱导。这一结果表明,近端外阴前体细胞中的LET-23可能结合并隔离诱导信号LIN-3 EGF,从而阻止诱导信号扩散到远端外阴前体细胞。