3577.8.4 Conclusion
In some ways, the Temporal Gradient Model resembles John Saunders’ (1919–2011)
Progress Zone Model for limb development (Saunders 1948 ). Saunders proposed that
limb bud mesenchymal cells in close proximity to an ectodermal structure called the
Apical Ectodermal Ridge (AER) are maintained in a proliferative state and that cells
adopt more distal fates the longer they remain under the influence under the AER. The
AER acts as a stable source of signals adjacent to a highly dynamic cell population,
analogous to the role proposed for the extraembryonic tissues of teleosts and mam-
mals in the Temporal Gradient Model of mesoderm induction. The main difference
between the two models is that in the Progress Zone Model, cell divisions push older
cells away from the influence of the AER, whereas in the Temporal Gradient Model,
active or passive cell movements bring cells into and/or out of the influence of Nodal
signals from the extraembryonic tissues, though cell division could also influence a
cell’s position in the Nodal gradient. The Progress Zone Model has fallen out of favor
recently, and other models may better explain proximo-distal axis formation in the
limb (for review, see Mariani 2010 ). Nonetheless, the model has provided a firm intel-
lectual framework to understand limb patterning. The Temporal gradient model pro-
vides a similar intellectual framework to understand how a reproducible pattern is
imposed on dynamic tissues, such as the teleost margin or amniote primitive streak.
The model may also apply to how other signaling molecules, like Sonic Hedgehog or
BMP, act to pattern other dynamic tissues such as the anteroposterior axis in the limb
or the dorsoventral axis of the embryo (Harfe et al. 2004 ; Tucker et al. 2008 ).
The classic Reaction-Diffusion model may better explain germ layer induction and
patterning in species like the amphibians. In these embryos, the presumptive mesoderm
and endoderm are spatially segregated at the blastoderm stage, and cell movements are
limited before gastrulation. The spatial gradient of Nodal-related proteins could then
impose a pattern on a static field of responding cells. Cells close to the source of Nodal
expression are exposed to a high Nodal-to-Lefty/Antivin ratio and adopt endodermal
fates while cells further from the source are exposed to low Nodal-to-Lefty/Antivin ratio
and adopt mesodermal fates. This suggests that the Nodal signal transduction pathway
can be adapted to pattern both static fields of cells as well as dynamic tissues. How this
occurs is not clear, but in theory the same mechanism that interprets the absolute dosage
of Nodal can also be used to interpret the total cumulative dose over time. It has already
been well established that cells constantly assess their exposure to a gradient of Activin-
like signals using a “ratchet- like” mechanism, in which cells can modulate to a higher
threshold response, but not to a lower threshold response (Gurdon et al. 1995 ).
7.9 Systems Biology of Germ Layer Differentiation
The differentiation of the germ layers is one of the earliest morphogenetic changes
that can be investigated quantitatively. There is a fundamental difference between
the initial process of germ layer cell differentiation, in which molecular processes
are dominant via the action of gene regulatory networks (GRNs), and the events
after gastrulation, in which physics also plays a major role.
7 Establishment of the Vertebrate Germ Layers