Molecular mechanism of size control in development and human diseases

Abstract

How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.

Figure 1

Hierarchy of size control.

Figure 2

Insulin/PI3K/TOR signaling pathways for cell size control. Upon binding of insulin/IGF to the receptors, a signal is relayed via PI3K, lipid (PIP2, PIP3) and protein kinases (PDK1, Akt, TOR, S6K) that finally causes cell growth by activating the translation machinery and protein synthesis. Different connecting lines represent pathways found or confirmed in Drosophila (······), mammals (−·−) or both (—). Lines with arrow-head means the gene stimulates downstream gene function, whereas lines with blunt line means the gene inhibits downstream gene function.

Figure 3

Rho, Rac, Ras and myc signaling pathways for cell growth control. Lines and symbols are as described in Figure 2.