The way in which a network of interacting genes control how
cells are organised into tissues has been revealed for the first
time by a collaboration between biomedical scientists working at
MRC's National Institute for Medical Research (NIMR; now part
of the Francis Crick Institute) and mathematicians from UCL,
London.
The researchers, led by Dr James Briscoe of NIMR, looked at the
way in which the spinal cord develops in embryos, asking what
controls the arrangement of the different types of nerve cells that
make up the cord. They found that an external signal, called 'Shh',
governs the specific pattern of cells in the tissue by triggering a
complex network of genes called transcription factors. Shh
activated some of transcription factors and these then deactivated
others. As a result only a subset of transcription factors were
active in any one cell, creating specific types of cells depending
on how much Shh they were exposed to.
Using this knowledge, Dr Karen Page's team at UCL created a
mathematical model that reconstructed the complex network of
interactions between the transcription factors. This allowed the
team to investigate the network in isolation from other parts of
the cell and confirmed that the network is responsible for the
pattern of cells in the spinal cord. It also revealed that the
structure of the network makes cells less susceptible to
fluctuations in Shh, locking-in the identity of cells so that they
don't change if Shh is decreased. This helps explain the embryonic
development of the spinal cord and suggests why it is so precise
and reliable.
Dr Page said: "Understanding how patterns of cells are produced
in embryonic tissues is one of the long standing questions in
development biology. But it's difficult to answer this question
with biology alone, as cells and tissues are very complex. Bringing
mathematical modelling to the problem gives us a chance to focus on
specific parts and systems within cells - really sharpening our
understanding of what is happening."
Dr Briscoe suggested that similar mechanisms are also likely to
be at work during the development of other tissues in the body:
"External signals and networks of transcription factors have been
found in many embryonic tissues. Although the identities of the
factors and the details of the networks differ, our work showing
that a network of interacting transcription factors can transform
an external signal into a complex pattern of different cell types
in the spinal cord, raises the possibility that similar strategies
are used in other tissues".
The study also opens the door to tissue engineering in the
future. Dr Briscoe said: "By learning how the nervous system is
built in embryos, we hope to be able to mimic these processes using
stem cells in the laboratory. This might allow us to produce nerve
tissue in a dish in order to study diseased and damaged nervous
systems and perhaps, one day, to repair them".
Original article: Nikolaos Balaskas, Ana Ribeiro, Jasmina
Panovska, Eric Dessaud, Noriaki Sasai, Karen M. Page, James
Briscoe, and Vanessa Ribes (2012)
Gene regulatory logic for
reading in the vertebrate neural tube the Sonic Hedgehog
signaling gradient
Cell,148:273-284.