Segmentation
Introduction
Segmentation
is an important concept in embryology. Early animals, for example nematodes or
very early insects, are built around a repeating pattern. The segments of later
insects are also repeated, but some have become specialised with modified legs,
mouth parts or wings. The evolution of these changes is recorded, to an extent,
within the genes responsible for early organisation and patterning of the
embryos of these animals.
A common
insect used for investigating and discussing embryol-gmentation in particular,
is the fruit fly, also known as rosophila melanogaster.
The cells of
the Drosophila embryo are initially organised along a craniocaudal axis
by a morphogen gradient (see Chapter 3 for a similar example of a morphogen
gradient). This is followed by the expression of different genes by the cells
of the embryo, but only in particular bands along its length. These are gap
genes (Figure 21.1). This banded pattern of gene expression becomes more
pro- nounced when pair rule genes are expressed in alternating stripes
by the cells of the embryo (Figure 21.2). This level of organisation is pushed
even further by the expression of segment polarity genes within those
segments (Figure 21.3).
Now that the
embryo is organised into similar segments, the cells of each segment need
further information from which morphogenesis will shape the appropriate
structures for each segment (e.g. a wing, or a leg).
Hox genes are genes that share a
similar homeobox domain of 180 base pairs, which encodes for a sequence
of 60 amino acids. The term ‘homeobox’ refers to the sequence of base pairs,
and the term ‘homeodomain’ refers to the section of protein that corre- sponds
to the homeobox. The homeodomain is highly conserved between genes and between
species, with small differences.
Hox genes
are involved in the very early specification of the segments of the embryo,
from which the development of morphologically different segments can occur.
They are expressed in bands along the length of the embryo (Figure 21.4), and
in vertebrates there are multiple, overlapping, similar sets of Hox genes
(clusters) that gives some redundancy and more complex organisation than
possible in the development of the fly. The Hox genes of Drosophila do
not have this redundancy, so knocking out Hox genes gives profound effects. A
common example is the Antennapedia mutant, in which the fly develops legs where
its antennae would normally form (Figure 21.5). The Hox gene that would
normally specify this segment is lost, the pattern is broken and the segment is
re‐specified.
Hox genes
are found together on the same chromosome, lined up. Interestingly, they are
lined up in their order of expression along the craniocaudal axis. In humans
the 4 clusters of Hox genes are found on 4 different chromosomes.
The Hox
proteins that result from Hox gene expression are DNA binding transcription
factors, able to switch on cascades of genes. The homeodomain is the DNA
binding region of the protein.
All of this
organisation leads to the formation of visible early segmentation patterns
such as the somites (see Chapter 22), from which adult segmented structures
develop. In humans and other vertebrates the segmentation pattern can be seen
in the vertebrae, ribs, muscles and nervous innervation patterns (see Figure
22.5). These segments form sequentially, one pair after another.
Before
somites form, cells of the presomitic mesoderm display oscillating patterns of
gene expression, meaning the expression of genes switches on, off and on again
with time. This rhythmic expression of genes of the Notch pathways and their
targets is known as the segmentation clock. You can think of each cell hav- ing
its own clock and its own time.
A morphogen
gradient of fibroblast growth factor (FGF) and Wnt is secreted by cells at the
tail end of the presomitic meso- derm. You might call the edge of this
morphogen gradient the wavefront.
As cells at
the caudal end of the presomitic mesoderm proliferate and the tail grows, the
cells producing FGF and Wnt move further away from the head and from other
presomitic mesoderm cells. Some cells of the presomitic mesoderm no longer feel
the effects of FGF and Wnt as the wavefront moves away from them, and they
begin to form somites.
The band of
cells that leave the wavefront will either form the cranial end or the caudal
end of the somite depending upon the time of their segmentation clock at the
point at which they leave the wavefront. The temporal nature of the
segmentation clock is translated into the spatial arrangement of somites via
these mechanisms (Figure 21.6).
How the segmentation
clock works is still not entirely under-stood, but the understanding of these
mechanisms has developed remarkably over the last 15 years.
Through the
embryology of segmentation we can see the path of evolution and links between
vastly different animals, existing now and in prehistory, and the mechanisms
behind anatomical similari- ties amongst vertebrates. The giraffe, for example,
has 7 cervical vertebrae in its very long neck, just as we do in our much
shorter variant. While segmentation is clearly apparent in the bony structures
of adult anatomy, the embryology here helps us understand the arrangement of
many of the soft tissues too.
Clinical relevance
Minor errors
in segmentation can produce vertebral and intervertebral defects. A
wedge‐shaped hemivertebra may form, causing a form of congenital
scoliosis that worsens as the hemivertebra grows. A number of variations
have been documented. Other vertebrae may be fused completely, just laterally,
posteriorly or anteriorly, if the intervertebral space fails to form completely
osis or lordosis. Other developmental processes ay also cause
these deformities.
