Research Projects in the Chisholm lab

We are interested in the mechanisms of biological morphogenesis--how tissues achieve their shape and form in development. Many types of morphogenetic movement involve epithelia. The mechanisms underlying these movements are still poorly understood.

We are studying morphogenesis in a simple animal, the nematode worm Caenorhabditis elegans. C. elegans is an excellent organism in which to use genetic analysis to study morphogenesis for several reasons. First, worm genetics is rapid. Second, the worm genome has been completely sequenced, making molecular cloning of genes identified by mutation simple. Finally, many kinds of morphogenetic movements can be studied in the worm with single-cell resolution.

(For a review of how genetics has been used to study C. elegans morphogenesis, see Chin-Sang and Chisholm, 2000, Trends in Genetics 16: 544-551).

1. Patterning of the epidermis: the functions of Pax-6

Pax-6 family transcriptional regulators play key roles in development in many animals, in particular in eye development. In C. elegans the Pax-6 family member VAB-3 regulates cell fate specification and morphogenesis in the head (Chisholm and Horvitz, 1995, Nature 377: 52-55). C. elegans provides a model to analyze the Pax-6 regulatory hierarchy in an eyeless animal. We are currently studying how Pax-6 regulates target genes in morphogenesis using genetic and microarray approaches.

2. Epithelial sheet movements: Genetic dissection of Eph receptor tyrosine kinase signaling

Morphogenesis of the worm's epidermis provides a simple model for studying many aspects of epithelial morphogenesis. Epidermal 'enclosure' involves the spreading of a dorsal epithelial sheet around the embryo towards the ventral midline. Cell signaling within the neuronal substrate is necessary for these epithelial cell movements. We identified the Eph receptor tyrosine kinase VAB-1 and its ephrin ligands as important regulators of cell movements within the developing nervous system (George et al., 1998; Chin-Sang et al., 1999; Chin-Sang et al., 2002). We are using genetics to elucidate the Eph signaling pathway and parallel pathways regulating neuroblast movement in C. elegans. A LAR-like receptor tyrosine phosphatase, PTP-3, functions in parallel with VAB-1 signaling to control neural cell movements in the embryos (Harrington et al., 2002).

3. Control of epithelial cell shape: genetic dissection of the intermediate filament cytoskeleton

Elongation of the epidermis transforms the bean-shaped embryo into a worm. This is an example of how coordinated changes in cell shape can lead to tissue morphogenesis. We are interested in how the cytoskeleton of the epidermal cells is remodeled in this dramatic and coordinated shape change.

Using genetics we have found that subcellular structures known as trans-epidermal attachments are essential for epidermal elongation. Trans-epidermal attachments contain intermediate filaments and are equivalent to hemidesmosome-keratin systems of vertebrate epithelia. We showed that mutations in the intermediate filament protein IFB-1 cause abnormalities in elongation and defective epidermal integrity (Woo et al., 2004). The vab-19 gene is essential for epidermal elongation. VAB-19 encodes a novel ankyrin repeat protein that also localizes to trans-epidermal attachments (Ding et al 2003). Homologs of VAB-19 can be found in insects and in vertebrates, suggesting that the function of VAB-19 has been conserved in evolution.

Why are we doing this? one answer

Basic biological processes (genes, proteins, pathways) are often conserved in evolution. For example, all the genetic pathways described above are found in humans, and several are mutated in human diseases.

By understanding how these processes work in simple 'model' organisms such as C. elegans we may get a better understanding of their role in human development, both normal and pathological.

Another Answer

"It is strange that we are not able to inculcate into the minds of many men, the necessity of that distinction of my Lord Bacons, that there ought to be Experiments of Light, as well as of Fruit. It is their usual word, What solid good will come from thence? They are indeed to be commended for being so severe Exactors of goodness. And it were to be wished, that they would not only excercise this vigour, about Experiments, but on their own lives, and actions: that they would still question with themselves, in all that they do; What solid good will come from thence? But they are to know, that in so large, and so various an Art as this of Experiments, there are many degrees of usefulness: some may serve for real, and plain benefit, without much delight: some for teaching without apparent profit: some for light now and use thereafter; some only for ornament, and curiosity. If they will persist in contemning all Experiments, except those which bring with them immediate gain, and a present harvest: they may as well cavil at the Providence of God, that he has not made all the seasons of the year, to be times of mowing, reaping, and vintage."

Thomas Sprat (1667), The History of the Royal Society of London for the Improvement of Natural Knowledge