Like TGFβ itself, myostatin acts through the Smad intracellular signaling pathway (see Figure 15–57) to inhibit muscle growth specifically. Another intracellular signaling pathway, called the Hippo pathway, inhibits organ and organism growth more generally. It was discovered in Drosophila, but it operates in vertebrates as well. It inhibits growth both by promoting cell death (by blocking an apoptosis inhibitor) and by inhibiting cell-cycle progression (by inhibiting the expression of the cell-cycle gene Cyclin E). Some components of the pathway in Drosophila are shown in Figure 21–64. The organs of animals that are abnormally resistant to Hippo repression can grow to a monstrous size (Figure 21–65).
It is important to note that in all species nutritional conditions also play a fundamental part in regulating the pace and extent of growth, and in animals they do so through hormonal signal networks that are highly conserved between vertebrates and invertebrates. Although we do not have space for details here, genetic experiments, especially in Drosophila, have begun to unravel the logic of these controls, and to indicate how they may operate alongside other machinery, such as the Hippo pathway, to determine final size.
The sizes of animals and their organs vary widely and largely depend on total cell mass. This in turn depends on the size and number of cells, which are increased through cell growth and cell division, respectively. Cell numbers are reduced by programmed cell death. Each of these processes depends on both intracellular and
Figure 21–65 Overcoming Hippo repression increases organ size. (a) Livers from control and Yap-overexpressing mice. In these mice, hippo signaling is insufficient to block Yap. (B) adult heads from control and Yap-overexpressing flies. In the mutant flies, hippo signaling is unable to block Yap. (From J. Dong et al., Cell 130:1120–1133, 2007.With permission from elsevier.)
Figure 21–64 Hippo pathway. hippo, a protein kinase, limits growth by phosphorylation and activation of the kinase Warts, which in turn phosphorylates and inactivates the transcriptional coactivator Yorkie (called Yap in vertebrates). When unphosphorylated, Yorkie/Yap drives tissue growth: it activates the transcription of the growth-promoting gene Myc, the cell-cycle progression gene Cyclin E, the antiapoptotic gene Diap, and the microrNa Bantam. hippo-induced phosphorylation of Yorkie/Yap blocks this effect.
extracellular signals. The mystery is how these processes are regulated and coordinated to produce and maintain the characteristic final size of the adult organ or animal.
Some signals such as survival factors, growth factors, and mitogens stimulate growth by promoting cell survival, cell growth, and cell division, respectively, while other signal molecules do the opposite. Although most of these signals operate locally to help sculpt the size and shape of the animal, its organs, and appendages, others act as hormones to regulate the growth of the animal as a whole. Nutrients can regulate growth through hormonal signals in the entire body.
Many animals and organs can, by unknown mechanisms, assess their total cell mass and regulate it. If, for example, cell size is artificially increased or decreased in these cases, cell numbers adjust to maintain a normal total cell mass. Conversely, if cell numbers are artificially increased or decreased, cell size adjusts to compensate.