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a more negative potential blocks the secretion of neurotransmitters. The active state with a less negative potential permits secretion. The received neurotransmitter initiates a local opening of allosteric ion channels, and local depolarization, at one end of the resting neuron. Weak linkage is provided by the propagated change of membrane potential, activating the entire neuron. When the other end becomes activated, it initiates secretion. The input (receptors and ion channels) is largely independent of the output (the secretory mechanism), connected only by the propagated depolarization. Receptors and ion channels can be installed or removed without reconfiguring secretion, membrane polarization, or impulse propagation, which are all conserved. They do not have to coevolve. In this case weak linkage has probably facilitated the evolution of the large variety of receptors, ion channels, and nerve cell types.

A still more complex example of weak linkage is embryonic induction, a developmental process first described in 1924 by Spemann and Mangold. Here a small group of cells, the “organizer,” induces the development of the central nervous system in nearby cells of the rest of the vertebrate embryo. At the time, it was thought this induction must entail detailed instructions to the responding cells. A surprising discovery of the past decade is that the organizer acts by secreting a few inhibitors (antagonists) that do not even bind to the responding cells (De Robertis, 2006). Instead, they antagonize an inhibitory signal secreted and received by the nearby cells in a self-inhibitory circuit to block their development of the nervous system. The organizer, via its antagonist, disrupts the self-inhibition, and neurogenesis commences. Thus, a simple signal, which can easily be moved, replaced, or modulated, regulates the time, place, and amount of the very complex developmental response. The ease with which simple signals can entrain complex processes reflects the capacity of core processes to engage in weak regulatory linkage.

Finally, the action of enhancer binding proteins in eliciting or repressing transcription (a complex specific output) is an excellent example of weak linkage. Transcription factors bind to the genome and mobilize enzymes that modify chromatin; the factors do not directly contact the core transcriptional machinery and play no role in transcript elongation, only in the initiation decision. Because of weak linkage, cis-regulatory DNA sites at which transcription factors bind can be far from the transcription start site, in either orientation, and composed of numerous independently acting regions (Levine and Tjian, 2003).

Weak regulatory linkage is important in developmental plasticity, which West-Eberhard has persuasively argued is a frequent substrate for heritable regulatory cooption (West-Eberhard, 2003). This plasticity entails the choosing of alternative developmental pathways according to environmental inputs. Examples include male–female differences, learning,



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