The Cell as a Machine

Although the blueprint for the body is built into the DNA sequence, it is still mysterious how a single fertilized egg cell develops into the mature organism. In mammals, the microenvironment of cells is critical for their proper differentiation. This comes from the simple fact that killing cells in a tissue will not seriously alter the development of that tissue, i.e. neighboring cells rapidly fill the gaps both physically and functionally. In other words, the plan for differentiation of the cell is not cell-autonomous but comes from dynamic interactions of the cell with its neighboring cells and matrix. As the single cell becomes a multicellular structure, there are a number of very standard changes in shape that take place. These involve a dynamic mechanical feedback between individual cells and the surrounding tissue. At a protein level, stem cells express many different proteins, which allow them to respond to many different stimuli, and define their differentiation program accordingly. These stimuli will be received from the microenvironment as well as circulating hormones, and will activate a specific set of complex functions that allow the cell to progress to the next step in development. At later times the microenvironment provides mechanical as well as biochemical signals, making it very difficult to take cells out of the embryo and expect them to differentiate properly. Furthermore, mechanical changes in the tissue are critical for proper development, and can only occur through dynamic feedback between the cells, and an ill-defined organ shape parameter. There are a variety of tyrosine kinases that when mutated or deleted will cause major changes in the shape of an organ. Recent findings indicate that many tyrosine kinases are directly linked to mechanosensing, which can explain how they have been genetically linked to the pathways that define shape. As cells differentiate into one of the over 300 different cell types, the set of proteins that are expressed becomes limited. Further, there are major epigenetic changes in nuclei that involve the modification of chromatin to silence genes that are not needed for the specific cell type. Generally, the regularly transcribed genes will not be silenced, whereas those that are not expressed become silenced in heterochromatin. We will discuss how the differentiation process is controlled and how differentiation is manifested both at the cellular and nuclear level.