Board Member: 1997 - 1998
Regulation of nematode developmentHow does an adult animal develop from an egg? My laboratory is interested in how this remarkable feat of developmental regulation is accomplished. Our research focuses on development of the nematode Caenorhabditis elegans. Although this small roundworm is simple, its basic body plan is shared with many higher creatures, including humans. Our aim is to understand fundamental molecular mechanisms that establish body pattern and organ formation. This lowly worm turns out to be an ideal organism for in-depth molecular genetic investigations of these basic developmental controls at the level of individual cells.
Cell-cell interactions that control cell fate
During animal development, cells communicate with each other to influence cell proliferation, migration, and differentiation. A major goal in my laboratory is to understand in molecular detail how cell-cell interactions control cell fates. In C. elegans, a single somatic cell, called the distal tip cell, is responsible for formation of a neighboring tissue--the germ line. To learn how the distal tip cell induces this tissue, we began by identifying genes required for normal germline development. Among the many genes discovered, three stand out as central to the interaction between distal tip cell and germline precursorcells: glp-1, lag-1, and lag-2. We have now analyzed these three genes at the molecular level and found that they encode the basic components of a pathway that conveys information from the distal tip cell to the germ line. The lag-2 gene encodes a membrane protein (LAG-2) produced by the distal tip cell and is likely to be the distal tip cell signal; glp-1 encodes a membrane protein (GLP-1) present in the germ line and seems to be the receptor; and lag-1 encodes a transcription factor (LAG-1), which appears to be the downstream regulator that controls organ formation and differentiation. To put this in another way, lag-2, glp-1, and lag-1 serve the functions of signal, receiver, and output in the responding cell.
The molecular pathway that regulates the distal tip cell-germline interaction is used broadly during C. elegans development. In addition to controlling germline induction by the distal tip cell, glp-1 governs early embryonic induction and a glp-1 homolog called lin-12 controls several other cell interactions during larval development. We have found that lag-2 can signal to either glp-1 or to lin-12 and, similarly, that lag-1 can control fates downstream of either receptor. We have also found that glp-1 and lin-12 are functionally interchangeable. Therefore, essentially the same signal transduction pathway is used throughout development for controlling fates by communication between closely apposed cells.
The GLP/LAG pathway is conserved throughout the animal kingdom. In Drosophila, homologs of lag-1 and glp-1, called Delta and Notch respectively, function as signal and receptor in cell fate decisions, much as in worms. Furthermore, a fly homolog of lag-1, called Suppressor of Hairless, is a component of the Notch pathway in certain tissues. Vertebrate homologs of lag-2, glp-1, and lag-1 have also been found. Indeed, two vertebrate homologs of GLP-1, called murine int-3 and human TAN-1, can be mutated to an oncogenic form. Given the conservation between worms and flies of both pathway components and pathway function, it seems likely that the same molecular pathway will play a crucial role in mediating cell interactions during vertebrate development as well.
Regulation of anterior-posterior axis by translational control
How does an embryo know its head from its tail? In nematodes, this anterior-posterior axis can be recognized already at the two-cell stage of embryogenesis. However, the molecular mechanism for establishing such asymmetry has long been a mystery. We have discovered that GLP-1 (a membrane receptor, see previous paragraph) is present in the anterior, but not the posterior, blastomere of the two-cell embryo. In addition, we have learned that this GLP-1 asymmetry is controlled at the translational level. Messenger RNAs present in the posterior blastomere fail to generate GLPL-1 protein due to translational control elements located in the 3' untranslated region (3'UTR) of the glp-1 maternal transcript.
The control governing GLP-1 asymmetry in nematodes may represent a more general mechanism for establishing asymmetry along the anterior-posterior axis of many embryos. This idea is based on the striking similarities between regulation of GLP-1 asymmetry in C. elegans embryos and that of hunchback aysmmetry in Drosophila embryos. Both hunchback and GLP-1 proteins are limited to the anterior and both are spatially restricted, at least in part, by translational control. Based on the parallels between hunchback and GLP-1, we have speculated that translational regulation may be a primitive molecular mechanism for regulating asymmetry along the anterior-posterior axis of many metazoan embryos.
Control of sexual differentiation
Most animals develop as either male or female. C. elegans makes this same basic sexual decision with an interesting twist. This worm develops as either hermaphrodite or male, where a hermaphrodite is essentially a female who first makes sperm (a male fate) and then switches to oogenesis (a female fate). The problem of determining sex in C. elegans therefore encompasses two problems: How is the organism as a whole specified as one sex or the other, and how is an individual tissue specified as male or female? My laboratory has addressed both questions. We have shown that one globally acting sex determination gene, called tra-2, encodes a membrane protein, which coordinates adjacent cells to adopt the same sexual fate. In addition, we have identified two tissue-specific genes, fog-1 and fog-3 which specify germ cells as sperm instead of oocytes. Finally, we have shown that post-transcriptional controls establish the XX germ line as hermaphorodite rather than female. The sex-determining genes, tra-2 and fem-3, are regulated first for the onset of spermatogenesis and then for the switch from spermatogenesis to oogenesis.