The Questions of Developmental Biology

*There is considerable debate as to how far paracrine factors can operate. Activin, for instance, can diffuse over many
cell diameters and can induce different sets of genes at different concentrations (Gurdon et al. 1994, 1995). The Vg1,
BMP4, and Nodal proteins, however, probably work only on their adjacent neighbors (Jones et al. 1996; Reilly and
Melton 1996). These factors may induce the expression of other short-range factors from these neighbors, and a
cascade of paracrine inductions can be initiated.
In addition to endocrine, paracrine, and juxtacrine regulation, there is also autocrine regulation. Autocrine regulation
occurs when the same cells that secrete paracrine factors also respond to them. In this case, the cell synthesizes a
molecule for which it has its own receptor. Although autocrine regulation is not common, it is seen in placental
cytotrophoblast cells; these cells synthesize and secrete platelet-derived growth factor, whose receptor is on the
cytotrophoblast cell membrane (Goustin et al. 1985). The result is the explosive proliferation of that tissue.
Yes, it is named after the Sega Genesis character. The original hedgehog gene was found in Drosophila, in which
genes are named after their mutant phenotype. The loss-of-function hedgehog mutation in Drosophila causes the fly
embryo to be covered with pointy denticles on its cuticle. Hence, it looks like a hedgehog. The vertebrate hedgehog
genes were discovered by searching chick gene libraries with probes that would find sequences similar to that of the
fruit fly hedgehog gene. Riddle and his colleagues in Cliff Tabin's laboratory (1993) discovered three genes
homologous to the Drosophila hedgehog. Two were named after species of hedgehogs, the third was named after the
cartoon character.
TGF stands for transforming growth factor. The designation superfamily is often given when each of the different
classes of molecules constitutes a "family." The members of a superfamily all have similar structures, but are not as
close as the molecules within a family are to one another.
Cell Surface Receptors and Their Signal Transduction Pathways
The paracrine factors are inducer proteins. We now turn to the molecules involved in the
response to induction. These molecules include the receptors in the membrane of the responding
cell, which binds the paracrine factor, and the cascade of interacting proteins that transmit a
signal through a pathway from the bound receptor to the nucleus. These pathways between the
cell membrane and the genome are called signal transduction pathways. Several types of signal
transduction pathways have been discovered, and we will outline some of the major ones here. As
you will see, they appear to be variations on a common and rather elegant theme: Each receptor
spans the cell membrane and has an extracellular region, a transmembrane region, and a
cytoplasmic region. When a ligand (the paracrine factor) binds its receptor in the extracellular
region, the ligand induces a conformational change in the receptor's structure. This shape change
is transmitted through the membrane and changes the shape of the cytoplasmic domains. The
conformational change in the cytoplasmic domains gives them enzymatic activity usually a
kinase activity that can use ATP to phosphorylate proteins, including the receptor molecule itself.
The active receptor can now catalyze reactions that phosphorylate other proteins, and this
phosphorylation activates their latent activities in turn. Eventually, the cascade of
phosphorylation activates a dormant transcription factor, which activates (or represses) a
particular set of genes.
The RTK pathway
The RTK signal transduction pathway was one of the first pathways to unite various areas
of developmental biology. Researchers studying Drosophila eyes, nematode vulvae, and human
cancers found that they were all studying the same genes. The RTK-Ras pathway begins at the
cell surface, where a receptor tyrosine kinase (RTK) binds its specific ligand. Ligands that bind
to RTKs include the fibroblast growth factors, epidermal growth factors, platelet-derived growth
factors, and stem cell factor. Each RTK can bind only one or a small set of these ligands. (Stem
cell factor, for instance, will bind to only one RTK, the Kit protein.)