Introduction

What is Caenorhabditis elegans?

The roundworm (nematode) C. elegans has become one of the most popular model organisms in Developmental Biology. The broad range of genetic and molecular techniques that are available in C. elegans is one of the main reasons why this model organism has become so popular among many biologists. Today, over 3000 scientists worldwide are investigating the biology of C. elegans.
The research on this approximately 1 mm long roundworm that consists of fewer than 1000 body cells has revealed some fundamental and ubiquitous biological processes. One example is
 
the phenomenon of programmed cell death (Apoptosis). It was first described in C. elegans and found to be a genetically controlled process. Today, we know that programmed cell death occurs in most if not all animals and plants. Another example is the inactivation of gene expression through doublestranded RNA (RNAi or RNA interference) that was discovered in C. elegans. In addition, the study of C. elegans has provided important clues about the origins of human diseases such as Cancer or Alzheimer. Several human genes that play a key role in the formation of these diseases have their counterparts (homologs) in C. elegans. By studying the C. elegans homologs of human disease genes we can investigate the molecular mechanisms that cause the corresponding diseases in humans. Such experiments may ultimately lead to the development of new therapies and drugs.
To learn more about C. elegans and its "inventor" Sydney Brenner, see
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2002/brenner.html

Introduction - Developmental Biology and human Diseases

Over the past twenty years, Developmental Biology has become a very popular field in modern Biology. One main reason for the success of the "Developmental" approach to Biology is that researchers have focussed their efforts on a small number of model organisms that can be studied in the laboratory. This strategy has resulted in an almost exponential increase in our knowledge about the genes that control the normal development of animals and plants.
Today, Developmental Biologists study the following animal models: the roundworm Caenorhabditis elegans , the fruit fly Drosophila melanogaster , the Zebrafish Danio rerio , the claw-toed frog Xenopus laevis , the chick and the mouse. For some questions, in particular those addressing the functions of individual cells, the yeast Saccharomyces cerevisae and Saccharomyces pombe
complement the group of model organisms. Model organisms can easily be kept in the laboratory and one can use a broad range of genetic and molecular techniques to examine them. This faciliates the investigation of the central question in Developmental Biology:

Introduction - How do genes control the development of a singel cell, the fertilized egg cell, into a multi-cellular organism?

Almost eighty years ago, the German biologists Hilde Mangold and Hans Spemann observed that during the development of amphibian embryos certain groups of cells trigger a specific developmental programs (cell fates) in their neighboring cells. They called this phenomenon "induction" and the inducing cell group "organizer".

The Mangold-Spemann experiment

Ausschnitt aus einer Originalzeichnung von Hilde Mangold und Hans Spemann, 1924

click the picture

In the last twenty years, many of the genes that mediate the inductive signals have been discovered. They do not act on their own but rather in modules that constitute the intercellular signaling pathways and mediate intercellular communication. The comparison of these signaling genes accross the different model organisms has revealed a high degree of functional and structural conservation. For example, a nematode that lacks a particular gene can be rescued by the introduction of the corresponding (homologous) mouse gene and vice versa. Even more surprising was the observation that homologous genes control the same processes during the development of diverse species, e.g. the same molecular mechanism specifies the dorsal and ventral sides in the fruit fly and the claw-toed frog embryo.

Introduction - Human disease genes: The wrong signals at the wrong time

Several human genes that are involved in the generation of various diseases have been identified. In the affected patients, these genes often carry mutations that perturb the normal function of the proteins they encode. However, it was soon realized that many the so called disease genes perform very important function during the normal development.
Well-studied examples are the oncogenes Ras (which is invoved in the formation of most kind of cancers) and ErbB-2 (in breast cancer) which are activated through specific point-mutations or the tumor suppressor genes Rb (in retinoblastoma), Patched (in basal cell carcinoma, a form of skin cancer) or APC (in coloctal, intestinal cancer, see figure) which are inactivated in tumors. During normal development, the same genes function in important signaling pathways: The ErbB-2 gene, for example, encodes a receptor protein that becomes activated when it binds specific growth factors at the surface of the cell. The RAS protein is localized at the inner side of the plasma membrane where it acts as a regulatory switch: RAS is activated by the signals from the receptor proteins at the cell surface, and it transmits these signals into the cytoplasm of the cell.

Another example is Alzheimer's disease. In patients with a hereditary form of Alzheimer's disease, mutations that inactivate the Presenilin gene have been found. While studying the development of the Nematode Caenorhabditis elegans the group of Iva Greenwald discovered that the Presenilin gene has an important role in regulating the so called Notch signaling pathway. Presenilin encodes an enzyme that cuts other proteins at specific sites. The Notch protein is a receptor that binds to specific signaling molecules (called Delta and Serrate) outside of the cells. When the Notch receptor interacts with a Delta or Serrate ligand, Presenilin cuts Notch into two pieces. The piece of Notch that is released inside the cell moves into the nucleus of the cell where it activates a specific set of genes. In the neurons of Alzheimer's patients however, the Presenilin protein does not function and proteins such as Amyloid Precursor Protein (APP) are not cut. As a consequence, the APP protein accumulates within the neurons and causes severe damage.
These examples illustrate how Developmental Biology can be a new approach to look at the origins of human diseases. Understanding the molecular and biochemical details of the signaling pathways that control the development of model organisms will be a key to find new approaches for the treatment of diseases like Cancer and Alzheimer's.