How can a single ligand–receptor pair cause so many changes in gene expression that it determines the pathway of differentiation not only of the cell itself but also of its neighbors? Fig. 20.25 shows the mechanisms in simplified form. On the left is the progenitor cell nearest the anchor cell, which receives the strongest EGF signal. Activation of the EGF receptor by the ligand initiates a process of signal transduction in the cytoplasm, in which the signal is transmitted from one protein to the next by means of proteins at each stage phosphorylating several others, which amplifies the signal at each stage (Chapter 9). The result of signal transduction is that a set of transcription factors is activated.

In the nucleus, the transcription factors activate transcription of genes for type 1 differentiation. The transcription factors also activate transcription of genes that prevent type 1 differentiation in neighboring cells, including the genes that produce another type of protein ligand, called Notch. The Notch ligand is a transmembrane protein that activates Notch receptors in the neighboring cells. Activation of the Notch receptor in these cells activates a signal transduction cascade in these cells, which results in transcription of the genes for type 2 differentiation. The cascade started by the binding of Notch also activates transcription of other genes whose products inhibit the EGF receptor. Inhibiting the EGF receptor in type 2 cells prevents EGF from eliciting a type 1 response in the type 2 cell. In addition, at the same time that the type 1 cell produces the Notch ligand, it produces proteins that inhibit its own Notch receptors, and this prevents Notch from initiating a type 2 response in the type 1 cell.

417

While vulva development in nematodes is a fairly simple example of the importance of ligand–receptor signaling in development, EGF and Notch ligands and their receptors are found in virtually all animals. They are among dozens of ligand–receptor pairs that have evolved as signaling mechanisms to regulate processes in cellular metabolism and development. Humans have several distinct but related gene families of EGF and Notch ligands and receptors. Human EGF is important in cell survival, proliferation, and differentiation. EGF functions in the differentiation and repair of multiple types of cells in the skin; it is present in all body fluids and helps regulate rapid metabolic responses to changing conditions. Human Notch ligands are involved in development of the nervous and immune systems as well as heart, pancreas, and bone. Abnormalities in EGF or Notch signaling are associated with many different types of cancer.

Therefore, just as we saw in our discussion of eye and flower development, the molecular players involved in development are often evolutionarily conserved across a wide range of organisms. This is true even of genes that we typically associate with disease, such as BRCA1 and BRCA2 and their link with cancer. These genes not only play a role in cell cycle control in the adult, but also in early development in many organisms. In fact, although heterozygous mutations in these genes predispose individuals to breast and ovarian cancers in humans, homozygous mutations are lethal in early embryonic stages. In Fig. 20.26, we focus on the BRCA1 gene to summarize key concepts about DNA replication, mutation, genetic variation, inheritance, gene regulation, and development.

418

419