Synthetic Morphogens and Pro-morphogens for Aided Tissue Regeneration - Biologically Responsive Biomaterials for Tissue Engineering - page 44

posterior to the embryo has been proposed. This gradient has been named the zone
of polarising activity (ZPA), the source of the signal that controls the pattern of
digits [ 2 ]. Although retinoic acid was early identified as the potential candidate for
this signalling activity, later secondary signals emerged which were identified as the
bone morphogenetic protein-2 (BMP2) that is the homologue of the invertebrate
dpp and the Sonic Hedgehog (Shh) that is the homologue of the invertebrate Hh [ 2 ] .
However, it has to be said that it is not yet clear if these factors really satisfy the
criteria established for the definition of morphogens (See Sect. 3.1 ).

3.3 Morphogen Long-Distance Transport

and Local Mechanisms

The need for morphogens to exert their function in a gradient-dependent fashion
has prompted a number of studies about the molecular basis generating these gra-
dients [ 1, 3, 6 ]. In particular, it is not clear how the diffusion of morphogens within
tissues is regulated. Developing tissues such as the epithelia can present a rela-
tively complex structure preventing an easy diffusion of macromolecules [ 1 ] . It has
been suggested that cell proliferation can contribute to long-distance targeting of
specific signals and that these signals can be internalised by intermediate cells by
endocytosis to be later released in the extracellular space (Fig. 3.1 , lower pathway)
[ 1 ]. This process is known as planar transcytosis. In addition, it has been suggested
that signal may diffuse in the extracellular space not as soluble molecules, but
forming complexes with cell surface macromolecules such as the heparan sulphate
proteoglycans (Fig. 3.1 , upper pathway) [ 1 ]. These are also claimed to directly
influence various aspects of the morphogen gradients including their movement,
signalling and traf fi cking [ 7 ]. A mathematical model for morphogen gradient for-
mation suggests that morphogens are synthesised in local regions to form long-
distance gradients through the binding to heparan sulphate proteoglycans chains
thus reaching target cells.
It is also known that molecular gradients within a tissue can take place without
the occurrence of molecular diffusion in the extracellular space [ 8 ] . It has been
suggested that cell-mediated degradation of morphogens can generate gradients
regardless of their ability to diffuse in the extracellular space. Transport from cell to
cell through gap junctions can also occur and cells could be the transport vehicle of
the molecule. These kinds of transport might enable the formation of gradients
of non-secreted molecules. Molecular gradients can also be formed by the dilu-
tion of the molecular content of cells that continuously divide and become displaced
away from a source.
It has been highlighted that for a morphogen gradient to effectively work, preci-
sion and robustness of the signalling are necessary [ 1 ] .
The level of precision that is required has not yet been clarified, but in the
Drosophila embryo there are evidences of signalling precision both at cellular and
nuclear level [ 9 ] .