Biology Reference
In-Depth Information
similar rates
[33]
. Community effect signaling could be
a very general mechanism underlying the remarkably
similar functions of contiguous individual cells within
common embryonic territories, and the GRN wiring
underlying it one of the features that allows for multicel-
lular territorial fate and function in development. An
interesting difference from inductive signaling is that since
it is essentially a maintenance device ensuring homoge-
neous function, in so far as regulatory state is concerned.
Thus, in the cases we know about it is not transient as is
inductive signaling, the fundamental role of which is to
change spatial regulatory state rather than to maintain it.
Morphogenesis, differentiation, cell cycle control
(growth): Thus far we have been concerned with the
upper-level control system for development, the product of
which is the plethora of unique regulatory states, dynam-
ically defining in potential functional terms each compo-
nent of the forming body plan. However, the vast majority
of the genes in the genome, all but a few percent, and the
vast majority of genes expressed in development, are not
regulatory genes. They are the effector genes that do the
cell biological work of development, expression of which
is controlled transcriptionally by regional regulatory states
as development proceeds. Eventually, the terminal regu-
latory states and the terminal cell type differentiations are
installed. Cell cycle and morphogenetic effector genes are
called into play early in embryogenesis, and progressively
more differentiation genes are expressed as development
proceeds. The cell cycle is driven by a series of enzymatic
steps which affect the mitotic cytoskeletal and DNA
replication apparatuses, homologous from yeast to man. In
development, the deployment of the cell cycle is controlled
transcriptionally, by preventing the expression of genes
encoding cell cycle repressors or causing expression of
genes activating the cycle at the appropriate times. These
control functions are executed as an output of the regula-
tory state of each growing domain of the embryo
[24]
.
A fascinating but largely unsolved aspect of development
is exactly how morphogenetic functions are called into
play, in a modular fashion, in given regulatory state
domains. That is, to effect a morphogenetic function many
separate cell biological functions have to be executed, and
the cells that build multicellular structures have to have
activated genes encoding the proteins that produce the
right physical functions to generate these structures. For
instance, in some animals the gastrular endoderm cells of
an invaginating embryonic gut must have cell surface
properties that enable them to slide over one another so as
to accomplish the formation of an elongated tube, and they
also have to have activated sets of genes encoding motility
functions. No one yet knows how many separate genes are
required to generate these phenotypes, but the number will
not be small. Nor is it clear whether a majority of such
genes in any given context have to be subject to direct
transcriptional control by the local regulatory state, or
alternatively, if most of these genes are widely expressed
and only a minority of 'checkpoint' genes that trigger or
nucleate the whole process have to be controlled directly
by the GRN, though there is some evidence for the latter
(for a review, see
[24]
). To solve morphogenetic control
mechanisms, we will have to identify the genes required to
make a tube, or an epithelium, or a bifurcation, or to
control cycling in a growing tissue, etc., and relate the
transcriptional control of those genes to the ambient
regulatory state. Differentiation is a somewhat discrete
regulatory problem, about which much more is known (for
a review, see
[24]
). Differentiated cells express sometimes
large sets of effector genes, the products of which are
together used to produce the specialized functions moun-
ted by these cells. Such differentiation gene batteries are
expressed only in given cell types, while in contrast all
cells sometimes execute cell division. Many different
kinds of cell use overlapping morphogenetic functions, for
instance those controlling cell motility, contractile
behavior, and so forth. Differentiation effector genes in
each battery are individually controlled at the transcription
level by a small subset of the factors present in a cell type-
specific regulatory state. Thus for differentiation gene
batteries, as opposed to the higher levels of control in the
GRN, wiring is largely parallel, in that many genes
respond to the same few cell type-specific inputs.
The adult body plan: Development of the body plan
terminates when there are no further body parts to be
formulated. But of course this is not the end of development,
broadly defined. There are in many animals extensive
changes in scale and size from juvenile to adult. Inmammals
these changes are massive, and as in postnatal human brain
development, they may be extremely complex but perhaps
still use the same mechanistic features of embryonic
development as do other body parts. In general, post-
embryonic developmental processes also involve the
peripheral aspects of developmental GRNs, such as the
continuing use of morphogenetic, differentiation and cell
cycle subprograms, in response to the terminal sets of spatial
regulatory states. As has become a prominent realization
lately, development in fact never terminates, as the differ-
entiation functions of stem cells throughout adult life attest.
But it is important to realize that stem cell re-creation of
injured muscle or liver, or even diversification of immune
cells from multipotential hematopoietic precursor cells, is
a wholly different phenomenon from embryonic develop-
ment of the body plan. Such adult stem cell differentiation is
like terminal differentiation in embryogenesis: it requires in
any given case relatively few specifically expressed regu-
latory factors, and it involves no novel spatial establishment
of regulatory states, the fundamental function that underlies
body plan development. Thus the genomic program for stem
cell differentiation is fundamentally different from the
