We still have very little idea how organisms or organs assess their total cell mass or monitor their own growth. Nevertheless, we are beginning to understand 1 meter some of the signal molecules that drive or halt growth in response to the mysterious cues that convey information about the size attained.
We have already seen how some signals act systemically as hormones to regulate the development of the animal as a whole. Some of these serve to regulate growth. In mammals, for instance, growth hormone (GH) is secreted by the pituitary gland into the bloodstream and stimulates growth throughout the body: excessive production of growth hormone leads to gigantism, and too little leads to dwarfism (Figure 21–61). Pituitary dwarfs have bodies and organs that are proportionately small, unlike achondroplastic dwarfs, for example, whose limbs are disproportionately short, usually because of a mutation in a gene encoding an FGF receptor that disrupts normal cartilage development (Figure 21–62).
Growth hormone stimulates growth largely by inducing the liver and other organs to produce insulin-like growth factor 1 (IGF1), which acts mainly as a local signal within many tissues to increase cell survival, cell growth, cell proliferation, or some combination of these, depending on the cell type. Large breeds of dogs such as Great Danes owe their great size to high levels of IGF1, while miniature breeds such as Chihuahuas have low levels (see Figure 21–57).
Not all growth-regulating extracellular signals stimulate growth; some inhibit it, by promoting cell death or inhibiting cell growth, cell division, or both. Myostatin is a TGFβ family member that specifically inhibits the growth and proliferation of myoblasts—the precursor cells that fuse to form the huge, multinucleated cells of skeletal muscle. When the Myostatin gene is deleted in mice, muscles grow to be several times larger than normal. Remarkably, two breeds of cattle that were bred for large muscles have both turned out to have mutations in the Myostatin gene; whippet dogs mutant for Myostatin develop similarly (Figure 21–63).
Figure 21–62 Achondroplasia. this type of dwarfism occurs in one of 10,000–100,000 births; in more than 99% of cases it results from a mutation at an identical site in the genome, corresponding to amino acid 380 in the FGF receptor FGFr3 (a glycine in the transmembrane domain). the mutation is dominant, and almost all cases are due to new, independently occurring mutations, implying an extraordinarily high mutation rate at this particular site in the genome. the defect in FGF signaling causes dwarfism by interfering with the growth of cartilage in developing long bones. (From Velasquez’s painting of Sebastian de Morra. © Museo del prado, Madrid.)
Figure 21–63 Myostatin limits muscle growth. a wild-type whippet dog and a bully whippet that lacks myostatin. (a, from http://www.merlinanimalrescue.co.uk/dogs/?m=201211; B, from http://animalslook.com/schwarzenegger-dog/.)