Molecular Control of Proliferation and Differentiation

247 Pages·1978·5.666 MB·English

by  John Papaconstantinou (Eds.)

MOLECULAR CONTROL OF PROLIFERATION
AND DIFFERENTIATION
The Thirty-Fifth Symposium of
The Society for Developmental Biology
Asilomar Conference Grounds
Asilomar, California
June 8-11, 1976
EXECUTIVE COMMITTEE
1975-1976
William J. Rutter, University of California, President
Donald D. Brown, Carnegie Institution of Washington, Past President
Ian M. Sussex, Yale University, President Designate
James A. Weston, University of Oregon, Secretary
Marie DiBerardino, Medical College of Pennsylvania, Treasurer
Virginia Walbot, Washington University, Member-at-Large
1976-1977
Ian M. Sussex, Yale University, President
William J. Rutter, University of California, Past President
Irwin R. Königsberg, University of Virginia, President Designate
Winifred W. Doane, Yale University, Secretary
Marie DiBerardino, Medical College of Pennsylvania, Treasurer
Virginia Walbot, Washington University, Member-at-Large
Business Manager
CLAUDIA FORET
P.O. BOX 43
Eliot, Maine 03903
Molecular Control
of Proliferation
and Differentiation
Edited by
John Papaconstantinou
Biology Division
Oak Ridge National Laboratory
Oak Ridge, Tennessee
William J. Rutter
Department of Biochemistry and Biophysics
University of California
San Francisco, California
®
1978
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List of Contributors
Boldface Denotes Chairmen
John W. Adamson, Hematology Research Laboratory, Veterans
Administration Hospital, Department of Medicine, University of
Washington School of Medicine, Seattle, Washington
T. D. Allen, Paterson Laboratories, Christie Hospital and Holt Radium
Institute, Manchester, M20 9BX, England
Edward A. Berger, Department of Biology, University of California,
San Diego, California
James E. Brown, Hematology Research Laboratory, Veterans
Administration Hospital, Department of Medicine, University of
Washington School of Medicine, Seattle, Washington
Graham Carpenter, Department of Biochemistry, Vanderbilt
University, Nashville, Tennessee
John M. Chirgwin, Department of Biochemistry and Biophysics,
University of California, San Francisco, California
Stanley Cohen, Department of Biochemistry, Vanderbilt University,
Nashville, Tennessee
T. M. Dexter, Paterson Laboratories, Christie Hospital and Holt
Radium Institute, Manchester, M20 9BX, England
Michael Feldman, Department of Cell Biology, The Weizmann
Institute of Science, Rehovot, Israel
Gideon Goldstein, Sloan-Kettering Institute for Cancer Research, New
York, New York
Denis Gospodarowicz, The Salk Institute for Biological Studies, San
Diego, California
ix
LIST OF CONTRIBUTORS
John D. Harding, Department of Biochemistry and Biophysics,
University of California, San Francisco, California
L. G. Lajtha, Paterson Laboratories, Christie Hospital and Holt
Radium Institute, Manchester, M20 9BX, England
S. Lan, Ontario Cancer Institute, Toronto, Ontario, Canada
E. A. McCulloch, Ontario Cancer Institute, Toronto, Canada
Raymond J. MacDonald, Department of Biochemistry and Biophysics,
University of California, San Francisco, California
Vivian L. MacKay, Waksman Institute of Microbiology, Rutgers
University, New Brunswick, New Jersey
Anthony L. Mescher, The Salk Institute for Biological Studies, San
Diego, California
Trudy O. Messmer, The Salk Institute for Biological Studies, San
Diego, California
Malcolm A. S. Moore, Sloan-Kettering Institute for Cancer Research,
New York, New York
John S. Moran, The Salk Institute for Biological Studies, San Diego,
California
U. Otten, Department of Pharmacology, Biocenter of the University,
Basel, Switzerland
Dieter Paul, The Salk Institute for Biological Studies, San Diego,
California
Raymond L. Pictet, Department of Biochemistry and Biophysics,
University of California, San Francisco, California
G. B. Price, Ontario Cancer Institute, Toronto, Ontario, Canada
Alan E. Przybyla, Department of Biochemistry and Biophysics,
University of California, San Francisco, California
Hans J. Ristow, The Salk Institute for Biological Studies, San Diego,
California
H. T. Rupniak, The Salk Institute for Biological Studies, San Diego,
California
LIST OF CONTRIBUTORS xi
William J. Rutter, Department of Biochemistry and Biophysics,
University of California, San Francisco, California
H. Chica Schaller, European Molecular Biology Laboratory,
Heidelberg, West Germany
M. Schwab, Department of Pharmacology, Biocenter of the University,
Basel, Switzerland
Eric M. Shooter, Department of Neurobiology, Stanford University
School of Medicine, Stanford, California
Solomon H. Snyder, Department of Pharmacology and Experimental
Therapeutics and Psychiatry and Behavioral Sciences, Johns
Hopkins University School of Medicine, Baltimore, Maryland
H. Thoenen, Department of Pharmacology, Biocenter of the
University, Basel, Switzerland
J. E. Till, Ontario Cancer Institute, Toronto, Ontario, Canada
Foreword
The 35th Symposium, "Molecular Control of Proliferation and Differentia-
tion," was held at Asilomar, Monterey Peninsula, California, June 8-11, 1976.
The Society gratefully acknowledges the efficiency and hospitality of the host
committee and the financial support from the National Science Foundation.
Approximately 300 people attended and enjoyed the science and the fellowship.
Special thanks are due Claudia and John Foret who carried out the detailed
arrangements for the meeting.
The Society for Developmental Biology
Xlll
Cell Communication in Embryological
Development: The Role of Distal and
Proximal Signals
William J. Rutter
Department of Biochemistry and Biophysics
University of California
San Francisco, California 94143
I. INTRODUCTION
A. Cells in a multicellular system interact in various ways:
A fundamental aspect of the division of metabolic labor existing in
pluricellular organisms is the production by certain cells of compounds that are
utilized or manipulated by other cells. For example the lactic acid produced by
anaerobic glycolysis during muscular exercise is a substrate for gluconeogenesis
in the liver and the kidney. End products of metabolism are usually detoxified
or modified for excretion by cells other than those which produce them. In
these instances the specificity of the interaction is derived from the complemen-
tarity of metabolic enzymes present in various differentiated cells.
The functions of particular cells may also be regulated by specific chemical
signals produced by other cells. In nervous systems cell communication is
mediated by neurotransmitters, some of which are listed in Table I. The
specificity of the regulation is provided by the neuronal network formed by the
effector cells that release neurotransmitters; these in turn trigger target cells
containing an appropriate surface receptor. Thus, stimulation of a variable
number of cells is achieved and the magnitude of the response is determined by
the number of cells involved. Hormone mediated regulation is similar in some
respects to nerve mediated responses but different in others. Hormones are
produced in cells usually at a distant site from the target organs and are
transported via the tissue fluids to the site of action. The target cells must
contain a specific receptor, and the magnitude of the response (as reflected in
the typical dose response curves) is determined by the degree of saturation of
available receptors.
In addition to communication through the extracellular fluid, direct cell
communication via gap junctions between neighboring cells has been demon-
3
4 WILLIAM J. RUTTER
TABLE 1
Neurotransmitters Function as Mediators
in Neuronal Networks
Acetylcholine
Epinephrine, Norepinephrine
Dopamine
7-Amino Butyric Acid
Serotonin
Glycine
(Glutamate)
strated (1). Only relatively small molecules can exchange readily through gap
junctions: There is effective exchange of metabolic intermediates, pleiotypic
regulators such as cyclic AMP, cyclic GMP and even small hormones but little if
any exchange of large molecular weight molecules. The biological function of
junctional complexes may be to integrate the physiological activities of cell
populations. Many of the cells in an early embryo are electrically coupled (2),
thus implying direct cell communication by junctional complexes. Later in
development, electrical coupling is more segregated, and may be restricted to
functioning units of similar cells. The direct transmission of information
molecules such as DNA or RNA to cells in tissue culture has also been reported
(3-6). The function if any of such nucleic acid transfer is unknown.
II. EVOLUTION OF CELL COMMUNICATION
A consideration of the possible evolutionary origin of cellular communica-
tion is instructive since it may provide a basis for correlating structural and
functional relationships among regulatory molecules. Primitive unicellular
organisms may have interacted largely at the nutritional level. The end
products of a given metabolic pathway in one species, may be the substrates
for a key pathway in another species. Metabolic dependence between cells
may then be stabilized by the production of a needed metabolite, e.g., a
needed precursor or coenzyme. In addition to metabolites cells may have
secreted hydrolytic enzymes such as proteinases or toxins in order to utilize
the products of other biological systems. Hormones may have been derived
from these proteins. Indeed, a structural resemblance has been proposed for
the serine proteinases and certain hormones (7). It is also possible that other
cell surface proteins, or partially hydrolyzed peptides might be employed as
signals.
The differentiation of cell surface structures may have occurred relatively
early in single cell systems. The individuality of the organism is frequently
expressed in its relationship with the external environment and the perception
DISTAL AND PROXIMAL SIGNALS IN DEVELOPMENT 5
of that environment can be altered by modification of the surface. The
aggregation of cells might alter the environment; for example, cell aggregates
with complementary metabolic processes should be more nutritionally
efficient since great dilution of metabolic intermediates would be precluded.
In such systems control of cell proliferation or of function may at first have
been related to the balance required for efficient metabolism of the available
substrates; but ultimately not only metabolic functions but motility, percep-
tion of environmental signals, etc. were segregated in various cells in the
population. In such multicellular systems communication between cells would
confer a selective advantage in order to control the relative proportions of
cells as well as the functions of those cells. In a system having n cell types the
number of signals required for independent non-redundant communication
among each cell is n!/n-2! = n(n-l). Thus the number of regulatory signals in
a complex organism might be very large. A multicellular system containing
100 cell types would require 9900 regulatory signals. Additional regulatory
events associated with integration of functions, development and redundancy
of crucial regulatory functions could increase the number substantially, such
that a large proportion of the genome might be devoted to regulatory as opposed
to direct physiological functions. There is no evidence that this is the case, in
fact there are arguments against it (8-10). Furthermore, there is no evidence
suggesting that each cell type communicates directly with every other cell type.
A more simplified strategy involving subsets of cells is, more likely, involved.
Some of the hormones regulate metabolic processes in many cell types, others
regulate function in restricted types.
The strategies involved in regulation of mature cell functions may be
quite different from those involved in differentiative and morphogenetic
processes. In the former, regulation of the activities of groups of cells may be
effectively accomplished from centralized control tissues by neuronal and
hormonal mechanisms. In the differentiation and morphogenesis, the organiza-
tion of the cells into functioning units is a dominant consideration. Some
kinds of proximal regulation at the level of individual cells seems involved.
Distal regulation may also be involved especially if the cells are dispersed
throughout the body, e.g., blood cells.
III. DISTAL AND PROXIMAL REGULATION IN
EMBRYO LOGICAL DEVELOPMENT
The implementation of the developmental program in embryos is crucially
dependent upon cell interactions. The requirement for normal development of
complex culture media or the presence of other tissues or specific extracellular
factors leads to the thesis that both proliferation and differentiation is
controlled by molecular signals provided by other cells. In this manner the