Richard M. Losick is the Maria Moors Cabot Professor of Biology, a Harvard College Professor, and a Howard Hughes Medical Institute Professor in the Faculty of Arts & Sciences at Harvard University.  He received his A.B. in Chemistry at Princeton University and his Ph.D. in Biochemistry at the Massachusetts Institute of Technology.  Upon completion of his graduate work, Professor Losick was named a Junior Fellow of the Harvard Society of Fellows when he began his studies on RNA polymerase and the regulation of gene transcription in bacteria. Professor Losick is a past Chairman of the Departments of Cellular and Developmental Biology and Molecular and Cellular Biology at Harvard University. He received the Camille and Henry Dreyfuss Teacher-Scholar Award, and he is a member of the National Academy of Sciences, a Fellow of the American Academy of Arts and Sciences, a Member of the American Philosophical Society, a Fellow of the American Association for the Advancement of Science, a Fellow of the American Academy of Microbiology, and a former Visiting Scholar of the Phi Beta Kappa Society. He is the 2007 recipient of the Selman A. Waksman Award of the National Academy of Sciences and a 2009 recipient of the Canada Gairdner Award.

Abstract

How a Single Master Regulator Generates Multiple Cell types

Arnaud Chastanet, Dennis Vitkup, Guo-Cheng Yuan, Thomas M. Norman, Jun Liu and Richard Losick, Harvard University and Columbia University

The bacterium Bacillus subtilis responds to adverse nutritional conditions by forming an architecturally complex community consisting of three cell types: prey cells, cannibals, and spore formers.  The prey cells are destined to be killed by their siblings, the cannibals.  The cannibals produce toxins that kill the prey (fratricide), immunity proteins that protect the cannibals from killing themselves (suicide), and matrix components that bind the cells together in the community. Finally, the spore-formers metamorphose into a dormant cell type that is resistant to extremes of time and the environment.  Nutrient limitation triggers the phosphorylation of a DNA-binding protein called 0A via a phosphorelay.  Phosporylated 0A (0A~P) is a master regulator that orchestrates the appearance of all three cell types. How can a single regulator generate three kinds of cells?  We propose a simple explanation based on these considerations.  First, genes that govern toxin and matrix production, which have strong binding constants for 0A~P, are activated by low to moderate levels of 0A~P and are shut off at high levels of 0A~P. Second, genes that trigger spore formation, which have weak binding constants for 0A~P, require high levels of 0A~P to be expressed.  Third, the level of 0A~P increases over time but varies from cell to cell in a broadly heterogeneous manner, which we attribute to a high level of noise in the phosphorelay.  Thus, cells in the population with little or no 0A~P are prey as they are unable to express any of the genes characteristic of cannibalism and spore formation.  Cells with moderate levels of 0A~P express toxin, immunity and matrix genes and are cannibals. Finally, cells with a high, threshold level of 0A~P are spore formers.  DNA-binding constants and noise explain how a homogenous population of cells is able to diversify through the action of a single regulator.

Keywords

Noise, cell type, sporulation, B. subtilis