Control ff Co-Ordinated Cell Movement During Morphogenesis:
Experiments and Models
Cornelis Weijer, University of Dundee
Cell movement plays an important role in morphogenetic processes
such as gastrulation, neurulation and formation of the brain.
Its co-ordination most likely requires long range signalling,
however little is known about the signals and mechanisms involved.
We study the control of differential cell movement in an evolutionary
simple organism, the cellular slime mould Dictyostelium discoideum
which stands on the threshold between unicellular and multicelluar
life. At the vegetative stage the cells live as solitary amoebae
in the soil, which feed on bacteria and multiply by binary fission.
However under starvation conditions a multicellular developmental
cycle is induced in which up to 100,000 cells aggregate chemotactically
towards an aggregation centre to form a slug which then can
move to a new habitat where it forms a fruiting body, consisting
of a stalk supporting a spore head. The spores germinate and
the cycle starts again. During aggregation the cells communicate
over large distances via propagating waves of the chemoattractant
cyclic AMP. These waves are initiated in the aggregation centre
and propagate outwards as concentric or spiral waves, instructing
the cells to move towards the aggregation centre. We have developed
digital image processing methods to analyse the dynamics of
the wave propagation (cell-cell communication) process in vivo.
Novel image processing methods allow us to track individual
transformant cells expressing the green fluorescent protein
GFP as a cell type specific reporter gene. We analyse changes
in speed and direction of cell movement as well as changes in
cell shape at the single cell level in a multi cellular organism.
We have now shown that the same principles that govern aggregation,
i.e. spiral wave propagation and chemotactic cell movement,
also control the morphogenesis of the later developmental stages.
The mounds are characterised by multi-armed spirals while in
slugs the chemotactic signal propagates as a three dimensional
spiral wave in the front and transforms into planar waves in
the back. This transformation in wave shape results from differences
in the excitability of the prestalk and prespore cell types
located in the front and the back of the slug respectively.
These cells types arise first in random positions in the mound
and then sort out chemotactically to form an axial pattern in
the slug. This cell sorting then feeds back onto the wave propagation
system. We perform detailed model calculations to understand
how such complex wave forms can arise in three dimensional excitable
media and how the cell movement feeds back on the pattern of
wave propagation. This has given us some insight in the basic
cellular principles of multi-cellular cell sorting, i.e. cell
type specific differences in excitability as well as differences
in chemotactic responsiveness.
We are now analysing the consequences of perturbations of
the signalling mechanism on morphogenesis via the study wave
propagation and cell movement in cAMP receptor, G protein and
chemotaxis and motility mutants.