Integration Of Signals And Gene Controls

nherent in the full genome contained in most cells is the potential to form vastly diverse cell types, which perform an enormous variety of tasks. Each individual cell, however, employs only part of an organism's complete genetic repertoire. An array of external hormonal, metabolic, developmental, and environmental signals influence which genes a cell uses at any given time in its life span. Infections also can trigger many responses. A cell's response to an external signal largely depends on its properties including (1) the inventory, locations, and associations of its proteins and other molecules; (2) its shape and attachments to other cells; and (3) its chromatin structure, which facilitates or blocks access to particular genes. We can think of these properties as a cell's "memory" determined by its history and response to previous signals. Thus, for instance, a cell can respond to a signal only if it possesses a receptor for that signal. In addition, a cell typically receives more than one signal at a time: for example, a combination of transforming growth factor p (TGFp) and fibroblast growth factor (FGF), a hormone signal that is interpreted in light of the ambient temperature, or an electrical pulse that is modulated by local ionic conditions. The response to each signal, or condition, is often influenced by another one. This integration of signals can prevent inappropriate responses and permit more nuanced responses to multiple signals.

To understand a cell's response to one or more signals and the effect of its memory on this response, it is useful to monitor changes in the expression of all genes and changes in the locations of organelles, proteins, or other molecules. Signal-induced changes in the intracellular ionic environ

Dividing cells (blue) in the developing spinal cord will differentiate into neurons (red). Cells that were engineered to make a differentiation-inhibiting signal (green) cause persistent cell division and reduce the number of differentiated neurons at the left. [Sean G. Megason and Andrew P McMahon. Adapted from Sean G. Megason and Andrew P McMahon, 2002, Development 129:2087-2098.]

Dividing cells (blue) in the developing spinal cord will differentiate into neurons (red). Cells that were engineered to make a differentiation-inhibiting signal (green) cause persistent cell division and reduce the number of differentiated neurons at the left. [Sean G. Megason and Andrew P McMahon. Adapted from Sean G. Megason and Andrew P McMahon, 2002, Development 129:2087-2098.]

ment, membrane potential, and cell shape also may be relevant to a cell's response. Two serious limitations have hampered efforts to obtain such a comprehensive view of the nature of cell responses to external signals. First, usually only one or a few aspects of a cell's response to a signal is easily monitored; second, determining responses in living cells in "real time" poses many technical difficulties. Technological advances are beginning to solve these problems, although neither has been completely overcome.

The major question posed in this chapter is how a cell integrates multiple signals and responds in the context of

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