title: Cell lineages and the logic of proliferative control.
abstract: It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors ("chalones") may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives-what, precisely, is being controlled, and to what degree-and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE-the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue-fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules-such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator-may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA. adlander@uci.edu
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Lander
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Gokoffski
authors.forename: Frederic Y M
authors.initials: FY
authors.lastname: Wan
authors.forename: Qing
authors.initials: Q
authors.lastname: Nie
authors.forename: Anne L
authors.initials: AL
authors.lastname: Calof
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D050150:Chalones / Q000378:metabolism*; D025461:Feedback, Physiological; D055412:Growth Differentiation Factors / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009831:Olfactory Mucosa / Q000166:cytology / Q000502:physiology*; D018034:Olfactory Receptor Neurons / Q000166:cytology; D012038:Regeneration; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*
chemical_list: D050150:Chalones; D055412:Growth Differentiation Factors; D028341:Activins