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for the problem under discussion here. First, the next step
in the computed gene cascades occurs long before steady-
state levels in mRNAs for the input transcription factors
are ever achieved. Since the only way exact level control
can be achieved is by balancing in and out rates
examples from the sea urchin endomesoderm GRNs
demonstrate.
Endomesoderm Development in
S. purpuratus
that is,
e
Embryos
Very briefly, three cell lineages contribute to endodermal
and mesodermal cell types in the sea urchin embryo [57,
58] . Their dispositions and signaling interrelations are
indicated diagrammatically in Figure 11.4 A,B. The central
domain shown on the left produces the skeleton and the
concentrically adjacent domains shown on the right
( Figure 11.4 B) produce the mesoderm and the endoderm.
The skeletogenic cells are specified as discussed below,
with an initial maternal input localized from the beginning
in these cells. When they become specified they produce
two essential signals. The immediately adjacent cells
receive Signal1 ( Figure 11.4 A) and become mesoderm; the
future endoderm receives Signal2 but not Signal1. In the
following we discuss as examples of network-mediated
fate decisions how these different states of specification
arise.
Example 1: Use of Maternal Anisotropy to
Define a Zygotic Regulatory Compartment
Spatially restricted zygotic gene expression is first
observed in the skeletogenic precursors. The pmar1
regulatory gene is expressed specifically in these cells and
is the earliest specifically expressed zygotic transcription
factor in the GRN driving skeletogenic cell specification
[59] . Pmar1 gene expression in these cells is controlled by
two transcription factors which are present in the egg
cytoplasm inherited by these cells as cleavage begins
(maternal
synthesis and decay rates at steady state
this means that
the regulatory system of the sea urchin embryo cares little
about exact level and rate control. Indeed, comparisons
among different individuals frequently show two- to
threefold differences in transcription factor mRNA levels
[45] . It is a forward drive, not a level-sensitive dynamic
system. Therefore, it is only the kinetics with which newly
activated genes produce transcription factor messages, and
these mRNAs are translated to produce the factor proteins,
which should count in determining the step time. But it is
these same basic processes that obey the Q10 law, and the
step time can be computed in terms of
e
these very
processes. Second, the Bolouri
Davidson model predicted
a typical step time for the sea urchin system of about 3
hours. Thus the pace of the step time clock depends simply
on basic biosynthetic dynamics, and this explains how
a Q10 rule for development could apply, since in turn the
dynamics of developmental specification processes depend
directly on the rates of regulatory state changes, that is, on
step time. A contributing factor, as yet unexplained bio-
chemically, is the general quantitative similarity in regu-
latory gene transcription rates in this embryo, with only
a few outliers (as indicated by the measurements in ref.
[45] ). In summary, the global dynamics of GRN function
in embryogenesis may be more regular and less occult than
meets the eye.
e
63] . The example
shows how localized maternal regulatory factors result in
the initiation of a specific localized zygotic regulatory state
in the embryo.
Example 2: Double-Negative Gate Circuitry for
Spatial Restriction of the Skeletogenic Cell Fate
Insteadofsimplyactivatingother transcription factors in
the skeletogenic GRN, Pmar1 functions as a repressor.
Within the skeletogenic cells, Pmar1 transcriptionally
represses the expression of the hesc gene which encodes
another repressor. The hesc gene is under the control of
ubiquitous activators, so it is expressed in all other cells
of the embryo ( Figure 11.4 A, 'Spatial Circuit') [64] .Its
target genes at this early developmental stage encode
multiple transcription factors in the skeletogenic GRN
(Fig. 11.4C, tan and pink areas). In the skeletogenic cells,
because Pmar1 is expressed, hesc is repressed and these
skeletogenic regulatory genes are expressed. The
circuitry constitutes a double-negative logic gate. The use
of this double repression circuitry not only drives gene
input, Figure 11.4 A) [60
EXAMPLES OF GRN-MEDIATED SPATIAL
CONTROL IN DEVELOPMENT
The GRNs driving the specification of endomesoderm in
the first 30 hours of sea urchin embryo development have
been analyzed systematically. Genes encoding transcrip-
tion factors were identified in the entire genome based on
their homology to known transcription factor families in
other species [46
e
51] . Their spatial and temporal expres-
sion patterns served as the basis to generate a complete
candidate list for the GRNs driving the formation of each
specification domain in the early sea urchin embryo.
Regulatory interactions between network components were
subsequently identified in numerous morpholino perturba-
tion and cis-regulatory analyses
e
56] . The
resulting GRNs explain how individual cell fate specifica-
tion processes occur and elucidate all the individual regu-
latory control mechanisms contributing to the organization
of this developmental process. The level at which these
mechanisms actually control process is not always apparent
from a classic developmental biology perspective, as
[14,15,52
e
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