Biology Reference
In-Depth Information
heritable control programs. Thus thinking about the readout
of such control programs, i.e., the development of the body
plan, leads to thinking about the origins of their different
structures, i.e., evolution of the body plan, and vice versa.
Here we can consider only the basic, common features of
the mechanisms by which readout of the genomic control
program is transformed into development of the animal
body plan, as we have discussed elsewhere
[22]
. Although
it lies outside our current province, deep understanding of
the developmental control programs of animals will ulti-
mately require understanding where they came from and
how they were assembled in geologic deep time.
The most important thing to know about any complex
progressive process is the principles by which its control
system operates. As the previous sections illustrate,
understanding the system-wide logic of GRN operation
should provide a sufficient explanation for why develop-
ment works as it does, in the ultimate terms of genomic
regulatory information.
In the following is an outline of the essence of the
developmental process as seen from the genomic perspec-
tive, deliberately devoid of detail and example, and designed
simply to highlight the levers by which the genomic control
program in principle produces development. This is inten-
ded for engineers rather than embryologists, logicians rather
than cytologists, systems bioscientists rather than those
focused on roles of specific genetic or biochemical functions
that are required for given developmental events. GRNs are
organized so as to control developmental process, and it is
therefore essential to recall what this process consists of.
Before the GRNs operate: functional roles of egg and
sperm: In the late 1870s and early 1880s it became clear
from observations of fertilization in the eggs of sea urchins,
plants, nematodes, and many other organisms that egg and
sperm contributed equally to the diploid genome of the new
organism that would develop from the fertilized egg
[1]
.
But this basic pillar of understanding does not capture the
asymmetry in functional roles of egg and sperm. In addition
to its nuclear components the egg cytoplasm contributes
much more. It contains a storehouse of all the housekeeping
components, proteins and mRNAs encoding common
structural and metabolic components, needed for any cell to
exist
[5]
. The amount of these in the storehouse is, roughly
speaking, enough to supply all the cells that the volume of
egg cytoplasm will be divided into during embryogenesis.
For until the embryo has become a larva able to feed, its
cells must rely on maternal nutrients and most other bulk
components needed for cellular life. We amniotes are an
exception, since our embryos can absorb nutrient from the
maternal environment.
The organization of the egg also determines the regu-
latory polarity of the embryo. Most regulatory factors are
universally distributed in the egg, so that they will be
present in all embryonic cells as cleavage divides it up.
However, there are always some factors of regulatory
significance which by early cleavage are anisotropically
distributed and are used to define the axes of the future
embryo
[19]
. These may be transcription factors, cofactors
thereof, or signaling components, which ultimately lead to
activation of genes encoding transcription factors. When
the cleavage planes divide up the egg, they generate a few
specific domains that are distinct in their regulatory
potentiality. Thus the founder cells of some specific cell
lineages, or those populations of cells in given topological
positions in the embryo, initiate different GRNs because
they are endowed ab initio with different factors of regu-
latory significance, and these in turn operate to activate
different early regulatory genes. The regulatory anisot-
ropies of the egg provide the initial symmetry-breaking
functions of the embryo, though these initial asymmetries
account only for the very first crude regulatory distinctions
in the embryo.
Embryonic specification: 'Specification' is an antique
embryonic term with the fuzzy definition that it is the
process by which cells of an embryo begin to acquire
a particular fate. But for us it has a particular, sharp meaning:
it is the process by which cells of an embryo acquire a given
specific regulatory state. Specification is progressive: the
initial inputs into a localized GRN lead toward the definitive
regulatory state of that domain, but it always forms by
a series of successive transcriptional steps. As just
mentioned, owing to the anisotropic regulatory organization
of the egg, different early embryonic cells initiate develop-
ment by activating diverse regulatory genes
[23]
. But that is
just the beginning. After very early development, spatial
specification processes are all controlled by GRN circuit
functions. Intercellular signaling is the main device used to
define new spatial regulatory domains after the relatively
simple initial spatial regulatory patterns are installed. As we
stress in the following paragraphs, the generation and the
interpretation of signals are both encoded properties of
GRNs, and GRN circuitry contributes to spatial patterning of
regulatory state in many additional ways. Below we consider
several specific examples, and numerous particular GRN
subcircuits that execute spatial patterning functions have
been reviewed by us elsewhere
[21,24]
.Theseinvariably
involve transcriptional repression. Subcircuits that include
spatial activation of genes encoding transcriptional repres-
sors are used to set domain boundaries, to exclude alterna-
tive regulatory states in given domains and to define
specification domains. The specificity of these repression
functions is resident in the genomic cis-regulatory sequences
of regulatory genes, as these determine the location of
transcriptional repressor and activator target sites.
Signaling and regulatory state: For three-quarters of
a century, ever since Spemann, developmental biology has
been obsessed with signaling in embryogenesis. This was
perhaps to be expected, given the dramatic and easily
